Topic Highlight Open Access
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Biol Chem. Jun 26, 2011; 2(6): 146-160
Published online Jun 26, 2011. doi: 10.4331/wjbc.v2.i6.146
Vasoactive intestinal peptide signaling axis in human leukemia
Glenn Paul Dorsam, Keith Benton, Jarrett Failing, Department of Chemistry and Biochemistry, Center for Protease Research, North Dakota State University, Fargo, ND 58102, United States
Sandeep Batra, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Author contributions: Dorsam G and Batra S wrote and edited the review article; Benton K and Failing J were students in the Dorsam Laboratory whose work is highlighted, and who wrote portions of the manuscript, assisted with graphs and figures, and edited the final draft.
Supported by A NIH/NIDDK career award 1KO1 DK064828 to GPD, 2P20 RR015566 and P20 RR016741 from the National Center for Research Resources, a component of the National Institutes of Health
Correspondence to: Glenn Paul Dorsam, PhD, Department of Chemistry and Biochemistry, Center for Protease Research, North Dakota State University, 1230 Albrect Blvd., Fargo, ND 58102, United States.
Telephone: +1-701-2315388 Fax: +1-701-2318324
Received: March 22, 2011
Revised: May 3, 2011
Accepted: May 10, 2011
Published online: June 26, 2011


The vasoactive intestinal peptide (VIP) signaling axis constitutes a master “communication coordinator” between cells of the nervous and immune systems. To date, VIP and its two main receptors expressed in T lymphocytes, vasoactive intestinal peptide receptor (VPAC)1 and VPAC2, mediate critical cellular functions regulating adaptive immunity, including arresting CD4 T cells in G1 of the cell cycle, protection from apoptosis and a potent chemotactic recruiter of T cells to the mucosa associated lymphoid compartment of the gastrointestinal tissues. Since the discovery of VIP in 1970, followed by the cloning of VPAC1 and VPAC2 in the early 1990s, this signaling axis has been associated with common human cancers, including leukemia. This review highlights the present day knowledge of the VIP ligand and its receptor expression profile in T cell leukemia and cell lines. Also, there will be a discussion describing how the anti-leukemic DNA binding transcription factor, Ikaros, regulates VIP receptor expression in primary human CD4 T lymphocytes and T cell lymphoblastic cell lines (e.g. Hut-78). Lastly, future goals will be mentioned that are expected to uncover the role of how the VIP signaling axis contributes to human leukemogenesis, and to establish whether the VIP receptor signature expressed by leukemic blasts can provide therapeutic and/or diagnostic information.

Key Words: Neuropeptides, Ikaros, Cancer, Hut-78, Epigenetics


Vasoactive intestinal peptide (VIP) is a 3.3 kDa protein originally discovered in swine intestines by Said et al[1]. Upon characterization, this small peptide consisting of 28 amino acids, had vasoactive properties when added to arteries, which prompted its name, VIP. Within 10 years after its discovery in 1970, VIP detection was measured in a number of human and rodent blood cells, including mast cells[2], neutrophils[3], eosinophils[4], thymocytes[5] and T and B lymphocytes[6]. Additional discoveries revealed that biological fluids derived from immune-privileged organs (e.g. eye and spine) were rich in VIP[7], and importantly inhibited the proliferation of immune cells in mixed lymphocyte cultures[8]. Intriguingly, in addition to immune-privileged compartments that actively repeal immune cells, the immunosuppressive VIP peptide was also detected in secondary immune organs that actively recruit high numbers of immune cells. Two immune compartment examples are the mucosa associated lymphoid tissue (MALT) of the pulmonary and gastrointestinal tissues[9]. The immunoreactive (IR) VIP nerves detected within these compartments co-stained with markers for noradrenergic, non-cholinergic nerves that innervated these organs, thus identifying an additional neuronal source for the immunosuppressive VIP peptide, in addition to certain immune cells, including developing thymocytes, activated T cells and mast calls[5,10,11].

These studies detecting IR VIP+ nerves within the eye and MALT represented the first major discovery that firmly established an anatomical basis for a neuroendocrine-immune network. Additional observations confirmed IR-VIP+ nerves innervating additional immune organs, including the thymus, spleen, bone marrow, skin and Peyer’s Patches within the gastrointestinal mucosa associated tissue. A second major contribution was the discovery that both immune and non-immune cells, in proximity to VIP+ nerve endings, expressed receptors for the VIP neuropeptide[12]. A third important observation was that VIP possessed chemotactic properties for resting T lymphocytes and actively recruited them to Peyer’s Patches located in the gut[13,14]. Lastly, VIP suppressed T lymphocyte activation by blocking interleukin (IL)-2, IL-4 and interferon (IFN)-γ production, inhibited apoptosis thereby enhancing Th2 memory cells and promoted the inducible FoxP3+ regulatory T cell (iTreg) lineage (Figure 1). This collective body of research is the fundamental core for the field called neuroimmunomodulation, of which VIP has been firmly established as a master mediator in this regulatory axis (for review see[15-17]).

Figure 1
Figure 1 Neuroimmunomodulation by vasoactive intestinal peptide. A: Vasoactive intestinal peptide (VIP) is delivered to primary (10) and secondary (20) immune organs by the peripheral nervous system (PNS), which affects the metabolism of cells in close proximity through its vasoactive properties (vascular smooth muscle cells) and its chemotactic activities on resting T lymphocytes. During TCR signaling, VIP is immunosuppressive directly on T lymphocytes by: inhibiting proinflammatory cytokine secretion/production, inhibiting apoptosis and promoting FoxP3+ inducible T regulatory cells; B: Delivery of VIP ligand to immune cells in indicated anatomical compartments (immune and non-immune) that represents a division of labor for VIP/vasoactive intestinal peptide receptor (VPAC)2 signaling (vasoactive; smooth muscle cells) and VIP/VPAC1 signaling (chemotactic and immunosuppressive; directly on lymphocytes) in an effort to effectively target trafficking naïve T cells to appropriate immune compartments such as Peyer’s Patches within the gut. MALT: Mucosa associated lymphoid tissue.

This review will focus on the VIP signaling axis and its relevance to human T cell leukemia. We will begin with a review of the VIP signaling axis in healthy T lymphocytes followed by the current understanding of VIP ligand and receptor expression profiles in T cell leukemia patients and cell lines. Penultimately, there will be a discussion on the contemporary dogma of the transcriptional regulation of VPAC1 by the anti-leukemic chromatin remodeling factor, Ikaros. Lastly, concluding comments will place into perspective a current working model that we expect will yield important insight into the potential role of the VIP signaling system in the diagnostic, treatment and clinical outcome of T cell acute lymphoblastic leukemia (ALL).


The ligand, VIP, is classified as a neuropeptide member of the secretin superfamily that performs crucial biological activities, including regulation of the immune system[18]. The secretin superfamily is made up of nine diverse small peptides that share similar, as well as, distinct biological activities. Cloning of the human VIP gene occurred in 1995 and is located on chromosome 6q25 (Entrez Gene ID 7432)[19]. Rat and mouse VIP genes had been previously cloned in 1991, and are positioned on syntenic regions of the rat chromosome 1p11 (Entrez Gene ID 117064) and on the mouse chromosome 10A1 (Entrez Gene ID 22353), respectively[20]. The structure of the human VIP gene consists of 7 exons interrupted by 6 introns and spans 9 kb. The VIP gene is translated into a 170 amino acid preproprotein and proteolytically tailored to generate at least two biologically active peptides, called VIP and peptide histidine methionine (PHM). Thus, the VIP gene appears to be organized into exon modules in which exon 5 exclusively encodes the VIP peptide, and exon 4 the PHM peptide (Figure 2). VIP shares nearly 70% amino acid sequence identity with another secretin family peptide called pituitary adenylate cyclase activating polypeptide (PACAP). The rodent (Adcyap1) (Entrez Gene ID mouse - 11516; rat - 24166), and human (ADCYAP1) (Entrez Gene ID 116) PACAP genes were cloned in the early 1990s[21-23], and have a similar gene structure and translational processing to VIP, generating at least three biologically active peptides called PACAP-38 (38 amino acids in length), PACAP-27 and PACAP related peptide. PACAP has remained nearly unchanged (96% identical) for over 700 million years of evolution and is considered the progenitor of the secretin superfamily of peptides[24]. PACAP-27 and VIP possess 68% amino acid sequence identity and VIP is thought to have evolved by exon duplication from PACAP concomitant with the evolution of the adaptive immune system as invertebrates evolved into vertebrates around 500 million years ago[24]. A co-evolution of VIP and its receptors with the establishment of the adaptive immune system may explain why VIP/PACAP modulates numerous immune functions such as proliferation[25], cytokine expression[26], inhibition of apoptosis[27] adhesion[14] and chemotaxis[13]. VIP is delivered by peripheral neurons to immune organs (and non-immune organs), in addition to being secreted by resting and activated leukocytes[28]. VIP is one of the most abundant peptides in immune organs such as the spleen, thymus and MALT[29]. This chemotactic and immunosuppressive neuropeptide ameliorates several autoimmune and inflammatory disease models in mice, including rheumatoid arthritis[30,31], atopic dermatitis[32], Crohn’s disease[33], multiple sclerosis (MS)[34] host vs graft disease, and antagonists to VIP receptors inhibit the proliferation of many common, solid-tissue, human cancers, including 51 of 56 human lung cancer cell lines[35]. Recently, VIP and PACAP were discovered to increase the generation of inducible CD4+/CD25+ regulatory T cells (iTregs) that are positive for FoxP3 expression[36].

Figure 2
Figure 2 Molecular biology of vasoactive intestinal peptide. A: Vasoactive intestinal peptide (VIP) is transcribed from a gene consisting of 7 exons and translated into a 170 amino acid prepropeptide that produces at least two biologically active peptides as shown; B: The amino acid comparison between pituitary adenylate cyclase activating polypeptide (PACAP)27 and VIP with bold letters representing identical amino acids between peptides, and asterisks indicating amino acid differences.
VIP receptors

The receptors that bind VIP and PACAP receive their name based on their affinity for these two biologically active peptides, respectively. For example, pituitary adenylate cyclase activating polypeptide receptor 1 (PAC1) binds PACAP with a 1000-fold greater affinity than VIP, and is therefore categorized as the selective VIP/PACAP receptor[24]. In addition to PAC1, there are two non-selective receptors that bind VIP and PACAP with equal affinity, called VIP/pituitary adenylate cyclase activating polypeptide receptor (VPAC)1 and VPAC2 (Figure 3). All three receptors share a presumed similar 7-transmembrane structure based on hydropathy plots, with three external (EC1-3) and three internal loops (IC1-3), an extended N-terminal extracellular ectodomain and a relatively short intracellular C-terminal domain[37,38]. The VPAC1 (Vpr1) and VPAC2 (Vpr2) genes were cloned in rodents (Vpr1 - Entrez Gene ID mouse - 22354; rat - 24875; Vpr2 - Entrez Gene ID mouse 22355; rat 29555) and humans (VPR1 - Entrez Gene ID - 7433; VPR2 - 7434) in the early 1990s, and have very similar genetic structures with the human VPAC1 gene consisting of 13 exons and 12 introns[39-41]. Human VPAC1 has been mapped to chromosome 3q22, and to a syntenic region on chromosome 9 in mouse. Upon ligand binding, VPAC1 and VPAC2 couple with at least three G proteins, including Gαs, Gαi and Gαq that regulate signaling molecules as diverse as adenylate cyclase, PKA, PKC, PLC, PLD and EPAC, and elevate the intracellular secondary messengers, cAMP, IP3, DAG and Ca2+, that appear to be largely cell-context dependent[17,42,43]. There is also solid evidence for nuclear factor κB dependent and independent signaling effects by VIP[44].

Figure 3
Figure 3 Binding selectivity of the vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide receptors. Pituitary adenylate cyclase activating polypeptide receptor 1 (PAC1) selectively binds pituitary adenylate cyclase activating polypeptide (PACAP) with 1000-fold greater affinity than vasoactive intestinal peptide (VIP), whereas vasoactive intestinal peptide receptor (VPAC)1 and VPAC2 bind VIP and PACAP with equal affinity.
VIP receptor expression profile and its transcriptome in T lymphocytes

In naïve, mouse and human CD4 and CD8 T lymphocytes, the constitutively expressed VPAC1 receptor is 300-500-fold higher than VPAC2[12,45-47] (unpublished data) at the mRNA and protein levels that appears to be inversely related to the expression level of IL-2. Our laboratory has recently identified the VIP/VPAC1 transcriptome in naïve and activated mouse splenic CD4 T cells. In naïve T cells, VIP/VPAC1 signaling appears to induce directed cell movement through EGFR signaling. In early activated T cells (5 h), the cAMP dependent CREM/ICER transcription factor is upregulated, which has been shown to “short-circuit” helix-loop-helix transcription factors that are critical for pro-inflammatory cytokine expression[48]. These microarray observations, we propose, can explain at a molecular level how the VIP signaling axis can act in an anti-inflammatory manner, as well as, induce the differentiation of activated T cells toward different effector phenotypes, including T regulatory cells and Th17 cells[36,49]. Since developing and mature T lymphocytes are heterogeneous cell populations, it will be important to generate the next generation of anti-VIP receptor antibodies capable of detecting protein within these hematopoietic subpopulations to confirm which receptor is evoking VIP-initiated signal transduction and altering metabolic cellular changes. To this end, our laboratory has generated by gene-gun technology a highly specific mouse anti-VPAC1 polyclonal antibody capable of detecting cell-surface VPAC1 protein on primary CD4 and CD8 T lymphocytes (manuscript submitted).

During in vitro T cell activation (e.g. anti-CD3/anti-CD28) T lymphocytes engage the cell cycle to begin a proliferative program that results in a precipitous drop of VPAC1 mRNA levels ≥ 80% as assessed by qPCR[46,47]. Likewise, in vivo activation of ovalbumin-specific CD8 T cells (OT-I) also showed undetectable levels (≥ 99%) of VPAC1 mRNA and protein using an adoptively transferred Th1 pathogen mouse model[50]. The mechanism for VPAC1 downregulation in mouse CD4 T cells is through a Src/ZAP70/JNK signaling pathway based on a pharmacological inhibitor study conducted by our laboratory[51]. Importantly, Anderson et al[52] recently demonstrated that VIP/VPAC1 signaling potently inhibited G1/S transition in human CD4 T cells. Thus, VPAC1 signaling appears to block the very signal (TCR activation) that causes its downregulation at the mRNA and protein levels, and might be the reason why many human and rodent T cell leukemia cell lines and human T cell blasts from patients with T cell leukemias have significantly reduced levels of VPAC1 mRNA (see below). After the expansion phase of antigen-specific CD8 T cells, we have collected data in mice that VPAC1 levels are restored in primary, but not secondary memory pools. These data may suggest an interesting possibility that the in vivo timing of VIP/VPAC1 signaling during T cell activation or in memory cells can have significant consequences regarding proliferative expansion or recruitment/retention in certain immune compartments based on the number of times exposed to antigen. In sharp contrast to VPAC1, VPAC2 has been termed the inducible VIP receptor, and was shown to become upregulated on Th2 cells, but not Th1 cells. A cause and effect for VPAC2 upregulation has been confirmed in its ability to protect Th2 cells from apoptosis and therefore is a survival factor and promoter of Th2 memory cells[53]. We have confirmed that mouse VPAC2 upregulation indeed does not take place in activated antigen-specific CD8 T cells during an in vivo Th1 pathogen, Listeria monocytogenes, infection[50]. This observation supports the idea that VPAC2 is induced against Th2, but not Th1, pathogens. Clinical relevance for VIP to skew towards a Th2 lymphocyte lineage is shown by amelioration of Th1-driven autoimmune disorders, including MS[34]. In summary, the timing and location of T cell activation is paramount to whether the VIP/VPAC1 signaling axis modulates the metabolism of the T cell population, as well as, whether VIP/VPAC2 signaling in Th2 cells can promote T cell survival.

VPAC receptor expression profile in hematopoiesis

Human hematopoietic stem cells that are enriched for CD34+ cells derived from either bone marrow or cord blood (CB) have been shown to predominately express VPAC1 verses VPAC2 as assessed by semi-quantitative PCR, subtractive hybridization and western analysis[54,55]. Also, the immature, non-dividing CD34+CD38- hematopoietic precursors express 4 times greater VPAC1 expression compared to the more mature CD4+CD38+ population, which contain elevated numbers of colony-forming cells (CFCs). The signaling induced by VPAC1 due to added VIP ligand (10-9 mol/L) to these hematopoietic stem precursor cells showed a synergic effect on myeloid and mixed colony growth of CD34+ CB cells with little to no detectable effect on BM cells in the presence, but not absence of three early cytokines, FLT3 ligand, stem cell factor (STF) and thrombopoietin (TPO)[55]. Another study confirmed high levels of VPAC1 mRNA in BM cells, but exogenously added VIP (10-13 to 10-7 mol/L) instead suppressed erythroid and myeloid colony growth, with a concomitant increase in transforming growth factor (TGF)-β and tumor necrosis factor (TNF)-α from an unidentified stromal cell type (possibly macrophages)[54]. These authors concluded that the suppressive activities by VIP/VPAC1 signaling was partly due to the increase in TGF-β and TNF-α as neutralizing antibodies to these cytokines suppressed the effect by VIP. These two studies did in fact validate functional VPAC1 expression in early hematopoietic populations. Their disagreement regarding a positive or negative influence on colony formation of CD34+ cells might be due to deriving these cells from different hematopoietic groups; bone marrow vs cord blood. Regardless, it was suggested that microenvironments immediately surrounding nerve endings that supply VIP in bone marrow would best allow for this neuropeptide to alter hematopoietic cellular growth as VIP is readily degraded in serum (10-11 mol/L), and the early cytokine signaling is inhibited by serum. Further research is needed to better understand the coordination power of VIP/VPAC1 signaling in the context of different hematopoietic microenvironments.

VPAC receptor expression profile during thymocyte development

It is agreed that peripheral, mature T cells from rodents and humans express higher levels of VPAC1 compared to VPAC2, however, there is some disagreement between their expression profile in developing mouse thymocytes, as well as, a potential species difference between rodents and humans[5,6,12,56-58]. Several labs have measured rat, mouse and human VPAC receptor mRNA by qPCR and RNase protection assays in thymocytes, and all agree on the expression of functionally active VIP receptors in total thymocytes. The discrepancy comes from distinguishing which VIP receptor, VPAC1 or VPAC2 (PAC1 is not expressed), was predominately expressed. Total thymocytes from rat and mouse revealed constitutive VPAC1 levels with increases in VPAC2 only upon TCR activation[5,57]. In contrast, human thymocytes showed greater VPAC2 verses VPAC1 mRNA expression, and TCR activation decreased VPAC1 but not VPAC2 mRNA message[58]. The latter study measured VPAC receptors by qPCR, which may account for the greater sensitivity for VPAC2 in the absence of TCR signaling, but does not explain the higher VPAC2 levels upon T cell activation. Additional studies further fractionated thymocytes into specific groups based on CD4 and CD8 expression. With the exception of rat double negative cells (CD4-CD8-, DN), double positive (CD4+CD8+, DP), single positive (CD4+CD8-, SP4) and SP8 subsets showed readily detectable VPAC1 mRNA message by PCR followed by southern hybridization confirmation[5]. This consistently high VPAC1:VPAC2 ratio in developing rat T cells was opposite for human thymocytes, which showed approximately 4-6-fold more VPAC2 mRNA compared to VPAC1 in DP, SP4 and SP8 subsets as assessed by qPCR[58]. DN cells contained low but equivalent levels of both receptors. These results suggest a species difference during T cell development. Furthermore, definite VIP receptor ratio discrepancies are seen within mouse thymocytes. For example, two studies using Balb/c mouse thymocyte subsets disagreed on the VPAC1:VPAC2 ratios in DN and SP8 thymocyte subsets. In contrast, their data did agree with respect to DP and SP4 subsets that showed higher VPAC2 vs VPAC1 mRNA levels[57,59]. These discrepancies can most likely be attributed to PCR primers used and/or experimental conditions such as media culture conditions. Our laboratory has collected data suggesting further discrepancies of VIP receptor expression in mouse thymocytes. Using the C57Bl/6 mouse strain instead of Balb/c mice, we detected more VPAC1 than VPAC2 in total thymocytes and greater VPAC1 than VPAC2 in all four major thymocyte populations: DN, DP, SP4 and SP8, respectively by qPCR (Manuscript submitted). In addition, we further subdivided this population based on CD44, CD25 and CD117 expression called DN1-4 subsets[60] that revealed a fascinating VIP receptor reversal with high VPAC1 mRNA expression found in the earliest T cell progenitor (CD44+/CD25-/CD117+, DN1) subset that became transiently silenced in DN2 (CD44+/CD25+) and DN3 (CD44-/CD25+) subsets with the concomitant induction of VPAC2 mRNA. DN4 cells showed the restoration back to high VPAC1 and low VPAC2 expression as observed for the later thymocyte populations. It is enticing to speculate that the VIP receptor ratio during T cell development may contribute to a Th1 skewing in C57BL/6 mice (high VPAC1:VPAC2) vs a Th2 skewing in Balb/c mice (low VPAC1:VPAC2). This idea is supported by the VPAC2 transgenic mouse model where forcing the expression of VPAC2 in a C57BL/6 Th1 skewed this mouse strain towards a Th2 phenotype[61] (see below). Functionally, two reports have shown evidence that VPAC2 mediates IL-2 suppression upon TCR activation in DP cells, and that VPAC2 signaling enhances DP→SP4 differentiation without altering apoptosis, viability, proliferation or cell numbers[57,59]. A third study revealed that VPAC1 signaling was contributing to the protection of spontaneous and glucocorticoid-induced apoptosis[62]. In summary, there appears to be functional VIP receptors expressed on developing thymocytes, but their expression ratio may be species specific, and VIP signaling influences IL-2 expression, differentiation and protection from apoptosis.

Genetically altered VPAC2 mice

While VPAC1 knockout and transgenic mice have not yet been reported, we and others have created VPAC2 knockout and transgenic C57BL/6 mouse strains. Opposite phenotypes were observed for the VPAC2 knockout and transgenic mouse models that provided further evidence for VIP/VPAC2 signaling playing an important role in immune responses[61,63]. Mice that developed in the absence of the immune-inducible VPAC2 receptor demonstrated enhanced delayed type hypersensitivity (DTH), which is mediated primarily by activated T cells and macrophages[63]. In contrast, there was a significant decrease in immediate type hypersensitivity (IH). These mice also demonstrated a polarization toward a Th1 response as evidenced by an increase in the Th1 cytokine, IFN-γ, and a decrease in Th2 cytokines, IL-4 and IL-5 as determined by ex vivo experiments of TCR stimulated VPAC2-/- CD4 T cells[63]. In VPAC2 transgenic mice under the control of the LCK promoter, VPAC2 protein was predominately expressed in the helper T cell compartment (25 fold higher in CD4 vs CD8 T cells). VPAC2 transgenic mice exhibited a shift in CD4 T cell polarization towards a Th2 phenotype as evidenced by (1) a depressed DTH response and an enhanced IH response; (2) an increased number of eosinophils and serum IgE and IgG1 levels; and (3) higher Th2 cytokines, IL-4 and IL-5, and lower Th1 cytokine, IFN-γ production by activated CD4 T cells[61]. Thus, VPAC2 significantly modulates CD4 T cell responses. VPAC1 expression levels were consistent with wild type levels in both genetically mutated mouse models. In review, VPAC2 knockout and transgenic mice show a reciprocal differentiation influence towards a Th2 polarization with respect to cytokine expression and delayed-type hypersensitivity through an unknown mechanism. In addition to Th2 differentiation, VIP/VPAC2 signaling protects Th2, but not Th1, cells from apoptosis and appears to contribute to this memory cell pool.

VIP-/- mice and immunity

The targeted removal of the VIP gene has been engineered[64-68]. A cadre of studies marshaled by James Waschek and other colleagues has focused on pulmonary disorders and asthma. These studies have uncovered an inflammatory component to the VIP-/- knockout mouse. Homozygous VIP-/- knockout mouse have enhanced lymphocyte and eosinophil infiltration into the lung. Moreover, microarray analyses have revealed that lung tissue in the absence of VIP show elevated inflammatory genes representing a chemokine (Ccr6), protease (Mcpt8) and two TNF superfamily members. These data suggest that VIP normally suppresses inflammation in tissues such as lung[68]. Evidence for similar inflammatory exacerbations in VIP-/- mice was observed in gastrointestinal disorders (Crohn’s disease) as well[69].

VIP signaling axis and cellular proliferation

The effect on cellular proliferation and cell cycle entry by the VIP signaling axis is complex. In rat neurons, it is well-established that VIP induces proliferation[70,71], whereas it is a potent inhibitor of proliferation in human vascular smooth muscle and CD4 T cells[52,68]. These apparent nonsensical influences toward cellular mitotic control is contributed to by the differential expression of at least three different receptors capable of binding VIP (VPAC1, VPAC2 and PAC1), as well as a fourth called formyl peptide receptor-like 1 (FPRL-1)[43]. Once bound, the ability for these receptors to engage signal transduction cascades is cell-specific as they differentially couple multiple G proteins[17]. VPAC1 expressed on a lymphoblastic T cell line (H9) can transmit alternate internal signals by differentially coupling to Gαs or Gαi based on whether PHM or VIP binds. However, irrespective of the particular G protein pathway activated, both ligands increased proliferation as assessed by BrdU incorporation[42]. The fact that VIP and PHM evoked different pathways suggests that VPAC1 (and possible other family receptors) can distinguish subtle residue differences in natural ligands thereby tailoring the signaling cascade elicited. In addition to VIP and PHM, activated mast cells and rat basophilic leukemia cell lines secrete a truncated VIP10-28 that acts as a potent VPAC1 antagonist, with low VPAC2 binding[11]. Couple this complexity to at least one splice variant of VPAC1, two for VPAC2 and 11 for PAC1, and the ability for the VIP ligand released by neurons innervating an immune organ can have a multitude of functional consequences[72,73]. Unpublished data from our laboratory has identified up to four additional VPAC1 splice variants present in lymphoid and brain cells. The VIP field, therefore, is in its infancy with respect to understanding the biochemical and cellular effects of the VIP signaling axis.

VIP signaling axis and T cell leukemia

VIP signaling is evident in most common types of human cancer, including breast, prostate, lung, and colon[74,75]. These cancer etiologies have been shown to predominately express functional VPAC1, with only the rare human leiomyomas expressing functional VPAC2 receptor. PAC1 receptors are typically expressed in paragangliomas, pheochromocytomas and endometrial carcinomas. Antagonists that inhibit all three VIP receptors have been shown to be effective at suppressing the proliferation of these common cancers, as well as, CNS, melanoma, ovarian and renal tumors and leukemia[35,76]. These reports indicate that VIP and their related peptides enhance the survival and/or promote cellular proliferation in most cancers. In contrast, the VIP receptor(s) responsible for promoting cellular proliferation has not been strenuously studied T cell leukemia. In 1992, Sue O’Dorisio’s group showed functional VIP binding sites that evoked increases in i[cAMP] levels in 22 out of a 32 patient cohort diagnosed with ALL of T or B cell origin[77]. The receptor identity, however, was unknown as the VIP receptors had yet to be cloned at the time of this study. Once the VIP receptors had been cloned later in the 1990’s, the identity of the VIP receptor(s) expressed in human T cell leukemia blasts could be determined. This research has been conducted primarily utilizing a handful of human leukemic T cell lines, including Stanford University Pediatric (SUP) T1, Molt-4b, Jurkat, Hut-78 and H9 lines (Table 1). Based on these four parent cell lines (H9 is a derivative of Hut-78 cells) there appears to be either high levels of VPAC2 mRNA expression (Sup T1 and Molt 4b with an immature phenotype), or low levels of both VPAC1 and VPAC2 mRNA (Jurkat, Hut-78 and H9 cells with a mature phenotype)[42,78-81]. Our laboratory has verified that CD4+/CD19- cells recovered from biopsied lymph tissue from 2 human T cell leukemia patients also expressed high levels of functional VPAC2 receptor with exceeding low levels of VPAC1 mRNA as assessed by qPCR and cAMP ELISA (manuscript in preparation). In rodent leukemia T cell lines of various etiologies, all cell lines studied exclusively expressed VPAC2, some of which were validated to be functional[57,82-84]. A VPAC2 predominant expression profile in cancer is unusual as VPAC2 expressing tumors are rare[74], and that the expression profile of healthy peripheral lymphocytes express extremely high VPAC1 at both the mRNA and protein levels[45]. Malignant T cells from ALL patients occur due to a blockade in thymocyte development (thymic in origin), or from a blockade in HSC within the bone marrow (prethymic)[85]. These hyperproliferating, low VPAC1:VPAC2 ratio expressing leukemic blasts egress from the thymus and enter the vasculature and bone marrow, where they co-mingle with healthy HSC (CD34+/CD38-) and peripheral mature T cells that all express high VPAC1:VPAC2 ratios (Figure 4). One possible explanation for a low VPAC1:VPAC2 ratio in human T cell leukemia blasts compared to healthy peripheral T cells, might be due to normally low VPAC1:VPAC2 expression during T cell development as human thymocytes were found to express much higher levels of VPAC2 compared to VPAC1[58]. This altered expression profile in leukemia blasts for the VIP receptor signaling axis could contribute to a growth advantage as VPAC1 is a potent G1/S transition arrestor by blocking the upregulation of several cyclins, while VPAC2 acts as a survival factor of mouse Th2 cells[36,52]. High levels of VIP ligand are also detected in human thymus. It is for these reasons the authors hypothesize that the increased expression of the VPAC2 receptor is a possible diagnostic marker for human (and rodent) T cell ALL. A similar supposition has previously been suggested by Waschek et al[82] where they rationalized that a potential molecular switch could take place during healthy T cell development, activation and/or homeostasis to explain the apparent VIP receptor reversal between healthy and leukemic T cells.

Table 1 Vasoactive intestinal peptide receptor expression in T cell lines.
Human T cell lines
Sup T1RT-PCR and NorthernVPAC2Xia et al[78] 1996
Molt-4bq-PCRVPAC2Summers et al[129] 2003
JurkatRT-PCR and q-PCR1Low levels of bothFinch et al[80] 1989
Hut-78RT-PCR and q-PCR1Low levels VPAC1 > VPAC2Xia et al[81] 1996
H9RT-PCRVPAC1Goursaud et al[42] 2005
Mouse T cell lines
EL-4.IL-2Northern/RT-PCRVPAC2Waschek et al[82] 1995, Xin et al[57] 1997
MBI-1.15NorthernVPAC2Waschek et al[82] 1995
BW5147NorthernVPAC2Waschek et al[82] 1995
CTLL-2NorthernNDWaschek et al[82] 1995
CTLL-MNorthernNDWaschek et al[82] 1995
DBA/2NorthernVPAC2Waschek et al[82] 1995
YAC-1NorthernNDWaschek et al[82] 1995
F10NorthernVPAC2Waschek et al[82] 1995
BL/VL3cAMPVPAC2Abello et al[83] 1989
NS8cAMPVPAC2Robberecht et al[130] 1989
TL-2cAMPVPAC2Robberecht et al[130] 1989
D10.TCR31RT-PCRVPAC2Xin et al[57] 1997
D10.G4.1RT-PCRVPAC2Xin et al[57] 1997
Rat T cell lines
GK 1.5RT-PCRVPAC2Xin et al[57] 1997
3.155RT-PCRVPAC2Xin et al[57] 1997
Figure 4
Figure 4 Working hypothetical model for differential vasoactive intestinal peptide receptor expression in T cell acute lymphoblastic leukemia blasts. The radical difference between low vasoactive intestinal peptide receptor (VPAC)1:VPAC2 ratio in developing thymocytes may act as a biomarker and prognostic indicator, readily distinguishable from peripheral hematopoietic stem cells (HSC) and mature T cells that express high VPAC1:VPAC2 ratios.

There is, however, some discrepancy with our proposal for high VPAC2 and low VPAC1 levels in ALL based on data showing human non-Hodgkin lymphoma patients exclusively expressing VPAC1 in 100% of the patient samples tested (6 out of 6)[75]. The authors did not distinguish between T vs B cell patients, however. Moreover, this study utilized ligand binding specificity for VIP receptor identification, which may contribute to discordant results compared to reverse transcription-polymerase chain reaction (RT-PCR) gene expression analysis, due to receptor internalization, dimerization and changes in ligand affinity[37]. Another study reported that Hut-78 T cells expressed 75 000 VPAC1 binding sites per cell based on RT-PCR, western analysis and 125I-VIP binding measurements[81]. This high VPAC1 expression level is not consistent with our qPCR data showing < 1% that of healthy CD4 T cells (manuscript in preparation), which have been estimated to have only approximately 15 000 binding sites[14]. Also, H9 cells, a derivative of Hut-78s, were also estimated to have fewer binding sites of approximately 10 000 sites per cell[42]. Therefore, the levels of VPAC1 in Hut-78 T cells in all likelihood are lower than healthy primary T cells, and that the report suggesting they contain high levels of VPAC1 expression (75 000 sites/cell) is perhaps an overestimation.

IK and its role in T cell leukemia

IK is a kruppel-like, zinc-finger transcription factor that functions as a master regulator for the development and maintenance of the hemo-lymphoid compartment[86-88]. The IK gene generates at least 11 isoforms through alternative splicing[89]. All IK isoforms have a common C-terminus containing an activation domain and two zinc fingers that facilitate dimerization with other IK isoforms. All Ikaros protein products (at least 11) differ in their N-terminal domain consisting of 4 zinc-fingers, three of which are necessary to bind DNA[90]. Of the three genetically modified IK mouse models that have been generated[91-93], the more severe model resulted in the complete arrest of fetal and adult lymphocyte development. Importantly, heterozygous mice developed an aggressive lymphoblastic leukemia (100% penetrance) 3 to 6 mo after birth[94]. In human leukemia patients, several reports have shown mutations in the IK gene[95-98]. More recently, it has been revealed that alternative splicing dysregulation alters the ratio between IK DNA binding to non-DNA binding isoforms[99]. Also, a 2009 study confirms that deletions/mutations in the IK gene is associated with a poor prognosis for B cell ALL patients[100], but interestingly IK mutations occurs a very small percentage of T cell ALL patients (≤ 4%)[101]. These mouse and human data have established IK as a master regulator for lymphopoiesis and an authentic tumor suppressor that sets the threshold for T cell activation, but indicates a species specific difference in Ikaros biology[102].

Mechanisms for transcriptional regulation by IK

Previous investigations in naïve mouse CD4 T cells have shown that IK recognizes at least five different chromatin remodeling and histone-modifying enzyme complexes. Regarding transcriptional permissive complexes, IK has been shown to bind the stimulatory chromatin remodeler, termed switch/sucrose nonfermentable[103]. Regarding transcriptional repressive complexes, IK has been shown to interact with the repressive nucleosome remodeling and deacetylase complex, c-terminal binding protein, c-terminal interacting protein, and mSin3a/b complexes[104-106]. Immunofluorescence staining shows IK protein present in a diffuse reticular nuclear pattern in naïve, non-cycling CD4 T cells. During T cell activation and entry into the cell cycle, IK is redistributed into a donut shaped nuclear pattern that co-localizes with pericentrimeric heterochromatin[86,107]. IK is differentially phosphorylated in a cell cycle dependent manner. The phosphorylation pattern of IK changes as T cells cycle from G1 to G2/M phase, and modulates DNA-binding affinity (36). IK is thought to act as an activator or repressor of gene expression based on its subnuclear distribution and binding partner(s) in naïve CD4 T cells[86,108]. There are also differences in basal Ikaros isoform expression levels between resting and activated mouse and human T cells. For example, mouse primary T cells express equivalent protein levels of IK-1 and IK-2 (IK-VI and IK-V based on Sinisa Dovat’s nomenclature) irrespective of the activation status of T cells. In contrast, human primary T cells clearly show low levels of IK-1 and the largest known Ikaros isoform, Ikaros-H, that are upregulated upon TCR signaling[109]. Moreover, Sinisa Dovat’s group has very nicely demonstrated how phosphorylation by casein kinase II and dephosphorylation by PP1 serves to regulate IK’s ability to bind DNA, regulate gene expression as well as dictate its subnuclear distribution[110,111].

Identification of Ikaros binding elements in the VIP receptor gene loci

VPAC1 and VPAC2 promoters possess a high frequency of putative Ikaros (IK) binding sites (5'-TGGGAT/A-3'). An inspection of a 5 kb nucleotide sequence of the human VPAC1 and VPAC2 promoters reveal 12 putative IK consensus sequences (5'-TGGGAA/T-3') spanning the transcriptional start site (Figure 5). In comparison, the rhodopsin gene that encodes a group I GPCR has only 1 putative IK binding site over a similar DNA length. Moreover, the entire gene loci of VPAC1 (55 kbp) and VPAC2 (48 kbp), including 10 kb immediately flanking these genes both upstream and downstream, possess 138 and 262 putative IK binding motifs, respectively. The random frequency of any 6 nucleotide DNA sequence being found on both strands of DNA in a 60 kb region is approximately 30 times. Using this random frequency as a comparison, there are 5-fold and 9-fold more IK consensus sequences present at these receptor gene loci. In addition, the IK binding elements are equally distributed throughout both VIP receptor loci with a nearly equal probability of finding an IK sequence on the template (60%) or non-template (40%) strand. Curiously, the 5 kb region mentioned above that spans the transcriptional start site for VPAC1 and VPAC2 has 12/12 (100%) and 8/12 (66%) IK binding motifs that are oriented on the non-template strand, respectively. We propose that this frequency of IK binding motifs preferentially on the non-template DNA strand is not a random event, but rather demarcates a powerful regulatory domain for Ikaros regulation of the VPAC1 and VPAC2 genes.

Figure 5
Figure 5 High Frequency IK binding sites at the vasoactive intestinal peptide receptor promoters. Schematic diagram of a 5 kb region for the vasoactive intestinal peptide receptor (VPAC)1 and VPAC2 promoters spanning the transcriptional start site (TSS). Red boxes are IK consensus sequences, with the number of IK binding sites per gene promoter indicated.
IK protein binds to the promoter regions of VPAC1

Evidence for IK protein binding to high-affinity IK-consensus elements in the promoter of VPAC1 is based primarily on electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation assays (ChIP). In 2002, we showed that nuclear protein from human Jurkat T cells, but not WI-38 fibroblasts, produced a retardation signal using a positive IK DNA probe (IKBS4[112]) or the most distal IK site within the VPAC1 promoter[113]. Jurkat protein was supershifted by anti-IK IgG but not a non-specific IgG confirming that IK protein was indeed part of the complex engaging the VPAC1 DNA probe. Moreover, recombinant GST-IK1 and IK2 bound to both probes and were competed away by unlabeled probe, further validating that IK protein could positively recognize and bind to the VPAC1 promoter. Subsequent EMSA studies further validated these observations using nuclear protein from human primary T cells. Interestingly, only nuclear extracts from activated CD4 T cells, but not resting cells, showed a retardation signal with the VPAC1 DNA probe. Anti-IK antibody supershifted this signal whereas IgG did not. Collectively, these data reveal that human recombinant and endogenous IK protein from either activated CD4 T cells or from malignant T cell lines can bind to IK-consensus sequences within the VPAC1 promoter in a sequence dependent manner. This observation was confirmed by in vivo ChIP assays that allows for a “snap shot” to be taken within a cell to determine protein/DNA interaction by forming reversible cross links with formaldehyde. This study supported the EMSA data revealing VPAC1 DNA amplification of immunoprecipitated chromatin using the anti-IK-CTS pAB, but not anti-IK-H or IgG negative controls[109]. That IK-1 is upregulated during T cell activation supports the notion that IK-1 engages the VPAC1 promoter resulting in its repression. Possible mechanisms to explain the differential binding affinity for IK-2 verses IK-1 dimers might be differences in consensus sequence recognition, subnuclear distribution or post-translational modification pattern changes that renders it not conducive to engage the VPAC1 promoter position in euchromatin (Figure 6)[51].

Figure 6
Figure 6 Ikaros engagement of the vasoactive intestinal peptide receptor 1 promoter in primary and T cell lines. Schematic representation of electrophoretic mobility shift assays and chromatin immunoprecipitation assays data comparing Ikaros engagement to the vasoactive intestinal peptide receptor (VPAC)1 promoter in primary CD4 T cells compared to the human lymphoblastic T cell line, Hut-78 cells. Top panels represent the expression profile for Ikaros in resting cells, and the bottom panels represent activated T cells.
Ikaros binding causes a functional change in VPAC1 expression

Using a negative IK cellular background of mouse NIH-3T3 cells, overexpression of DNA binding isoforms (IK-1 and IK-2), but not a DNA binding isoform that fails to enter the nucleus (IK-3), or the non-DNA binding isoform (IK-5), significantly downregulated VPAC1 expression by greater than 90% as assessed by qPCR[113]. These decreases in steady-state mRNA were paralleled at the protein level as well (50% decrease). Follow-up studies by our laboratory using a Hut-78 T lymphoblastic cell line background overexpressing the dominant negative IK-5 isoform introduced by nucleoporation resulted in a dramatic 15-fold induction of VPAC1 steady-state mRNA levels (manuscript in preparation, Figure 7). Surprisingly, the IK-2 DNA-binding isoform also increased VPAC1 levels by 2-fold, thus mimicking the positive upregulation that the DN IK-5 isoform displayed, albeit to a lower magnitude. These overexpression studies support a working model where decreasing the net DNA binding potential of the IK pool (IK-5), or altering the homo/heterodimer combination (IK-2, IK-H binds with greater affinity to IK-2 then IK-1[109]) results in greater IK-1 homodimers and causes elevated VPAC1 steady-state mRNA expression. We have unpublished data demonstrating IK enrichment to the VPAC1 promoter by ChIP assays in activated (PMA/ionomycin), but not resting, human Hut-78 T lymphoma cells could imply that dysregulating IK DNA binding by overexpressing IK isoforms result in increases in VPAC1 expression by an indirect manner. Future studies will investigate how IK dysregulation affects VPAC1 expression during T cell activation. We predict that VPAC1 expression will be silenced without functional IK DNA binding protein, which would support the idea that IK regulates transient gene expression changes and its plasticity upon resolution of T cell activation (memory cells).

Figure 7
Figure 7 Working model for Ikaros mediated regulation of vasoactive intestinal peptide receptor 1 expression. IK-5 overexpression results in the upregulation of vasoactive intestinal peptide receptor (VPAC)1 steady-state levels in resting Hut-78 cells. The DNA binding activity of Ikaros therefore can alter the expression of growth modulating genes like VPAC1 in a direct (binding to the VPAC1 gene) or indirect mechanism (regulating a repressor/activator that binds the VPAC1 gene). We predict VPAC1 silencing will occur in activated IK-5 overexpressing cells.
Elevated VPAC2 expression in the diagnosis and therapeutic intervention of human T cell ALL

There still remains a critical gap in the fundamental knowledge base regarding VIP ligand and receptor expression levels in human T cell ALL. It is becoming readily apparent that functional VPAC2 expression is elevated in rodent and human T cell blasts with an immature phenotype. Unfortunately, there are only a few reports documenting VIP receptor expression in human leukemia, and none to our knowledge have conducted molecular measurements of mRNA and protein expression levels. It will be imperative to collect qPCR and flow cytometry data from a large human T cell ALL cohort to confirm high VPAC2 expression to support its use as a diagnostic tool and/or drug target for this particular leukemia etiology. Moreover, parallel studies showing a concomitant reduction of VPAC1 levels in T cell ALL patient samples would further imply that a low VPAC1:VPAC2 receptor ratio could be utilized as a leukemic indicator for routine diagnosis. Also, the specific VPAC1:VPAC2 receptor signature could be used to follow a cohort of human T cell ALL patients in an attempt to determine the extent to which this receptor ratio can predict patient outcome. Absence of such research will continue to put these human leukemia patients at risk.

Ikaros and Notch regulation of the VIP receptors

The Ikaros transcription factor binds a 6 nucleotide DNA sequence that is identical to the Notch trimer complex[114]. An antagonistic competition between Ikaros (differentiation) and Notch signaling (proliferation) to gain access to DNA binding sites in gene targets is thought to control the T cell developmental plan in the thymus. Gain of function in Notch signaling is observed in 60% of human T cell ALL, which may shift the delicate equilibrium of differentiation/proliferation toward cellular division. Future research to identify whether the Notch DNA binding trimer is actively displacing Ikaros protein from the VPAC receptor loci (and other gene targets) is an important question to answer.

A growth advantage for T cell leukemia blasts with a low VPAC1:VPAC2 ratio

Investigations focusing on how low VPAC1:VPAC2 expression levels alter VIP signaling and whether this chemical information is interpreted by leukemic blasts to initiate a survival/proliferative cellular program is paramount to uncovering future therapeutic drug targets downstream of VIP receptors. Additionally, antagonists and agonists to VIP receptors can be used in combination with other known chemotherapy drugs in an attempt to obtain greater apoptosis induction in leukemia blasts.

Functional significance of VPAC receptor expression in human B cell ALL

Lastly, VIP receptor expression data needs to be collected from B cell ALL patients as Ikaros mutations/deletions have been deleted in 30% of these patients[100]. A decrease in Ikaros protein would increase the relative Notch trimer complex binding to gene targets, including the VIP receptor loci, and again potentially causing a hyperproliferative phenotype. These expression changes in VIP receptors may allow for prognostic prediction and future drug targets downstream of VIP receptors. That VIP and its receptors are also expressed in myeloid and erythroid blood cell lineages, future research focused on these leukemic etiologies is expected to result in important insight in combating these types of human leukemias as well.


Numerous studies have demonstrated that a number of human cancers overexpress VIP, or pituitary adenylate cyclase-activating peptide (PACAP) receptors[74,75,80,115]. Interestingly, VIP and PACAP analogs have been shown to affect tumor growth in in vitro and in vivo animal tumor models, suggesting that these receptors could be used as novel therapeutic targets or for localization of tumors[116-119]. The effect of VIP varies with the type of tumor, by either directly promoting tumor growth[76,120-122], suppressing growth[123], or promoting its differentiation through VPAC1 receptor signaling[124,125]. More recently, VIP has been shown to modulate tumor cell migration[125]. However, the role of the VIP signaling pathway in human leukemia is unknown, and only a few in vitro studies have examined the role of this signaling pathway in the survival of leukemic blasts[126]. VIP has been shown to modulate EGFR/HER2[120], VEGF[127,128], FOS expression[48] in breast cancer cell lines. These findings further underscore the importance of this signaling pathway in human cancer and warrants further investigation.


Peer reviewers: Wayne Grant Carter, PhD, School of Biomedical Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, NG7 2UH, United Kingdom; Johan Lennartsson, PhD, Ludwig Institute for Cancer Research, Uppsala University, Box 595, SE-751 24 Uppsala, Sweden

S- Editor Cheng JX L- Editor Kerr C E- Editor Zheng XM

1.  Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169:1217-1218.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Cutz E, Chan W, Track NS, Goth A, Said SI. Release of vasoactive intestinal polypeptide in mast cells by histamine liberators. Nature. 1978;275:661-662.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  O'Dorisio MS, O'Dorisio TM, Cataland S, Balcerzak SP. Vasoactive intestinal polypeptide as a biochemical marker for polymorphonuclear leukocytes. J Lab Clin Med. 1980;96:666-672.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Aliakbari J, Sreedharan SP, Turck CW, Goetzl EJ. Selective localization of vasoactive intestinal peptide and substance P in human eosinophils. Biochem Biophys Res Commun. 1987;148:1440-1445.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Delgado M, Martínez C, Leceta J, Garrido E, Gomariz RP. Differential VIP and VIP1 receptor gene expression in rat thymocyte subsets. Peptides. 1996;17:803-807.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Gomariz RP, Leceta J, Garrido E, Garrido T, Delgado M. Vasoactive intestinal peptide (VIP) mRNA expression in rat T and B lymphocytes. Regul Pept. 1994;50:177-184.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Taylor AW, Streilein JW, Cousins SW. Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. J Immunol. 1994;153:1080-1086.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Taylor AW, Streilein JW. Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation. 1996;3:112-118.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Bellinger DL, Lorton D, Brouxhon S, Felten S, Felten DL. The significance of vasoactive intestinal polypeptide (VIP) in immunomodulation. Adv Neuroimmunol. 1996;6:5-27.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Bellinger DL, Lorton D, Romano TD, Olschowka JA, Felten SY, Felten DL. Neuropeptide innervation of lymphoid organs. Ann N Y Acad Sci. 1990;594:17-33.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Goetzl EJ, Sreedharan SP, Turck CW. Structurally distinctive vasoactive intestinal peptides from rat basophilic leukemia cells. J Biol Chem. 1988;263:9083-9086.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Delgado M, Martinez C, Johnson MC, Gomariz RP, Ganea D. Differential expression of vasoactive intestinal peptide receptors 1 and 2 (VIP-R1 and VIP-R2) mRNA in murine lymphocytes. J Neuroimmunol. 1996;68:27-38.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Ottaway CA. In vitro alteration of receptors for vasoactive intestinal peptide changes the in vivo localization of mouse T cells. J Exp Med. 1984;160:1054-1069.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Johnston JA, Taub DD, Lloyd AR, Conlon K, Oppenheim JJ, Kevlin DJ. Human T lymphocyte chemotaxis and adhesion induced by vasoactive intestinal peptide. J Immunol. 1994;153:1762-1768.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev. 2004;56:249-290.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Smalley SG, Barrow PA, Foster N. Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its therapeutic potential in inflammatory disease. Clin Exp Immunol. 2009;157:225-234.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Dickson L, Finlayson K. VPAC and PAC receptors: From ligands to function. Pharmacol Ther. 2009;121:294-316.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Dorsam G, Voice J, Kong Y, Goetzl EJ. Vasoactive intestinal peptide mediation of development and functions of T lymphocytes. Ann N Y Acad Sci. 2000;921:79-91.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Tsukada T, Horovitch SJ, Montminy MR, Mandel G, Goodman RH. Structure of the human vasoactive intestinal polypeptide gene. DNA. 1985;4:293-300.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Lamperti ED, Rosen KM, Villa-Komaroff L. Characterization of the gene and messages for vasoactive intestinal polypeptide (VIP) in rat and mouse. Brain Res Mol Brain Res. 1991;9:217-231.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Hosoya M, Kimura C, Ogi K, Ohkubo S, Miyamoto Y, Kugoh H, Shimizu M, Onda H, Oshimura M, Arimura A. Structure of the human pituitary adenylate cyclase activating polypeptide (PACAP) gene. Biochim Biophys Acta. 1992;1129:199-206.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Cai Y, Xin X, Yamada T, Muramatsu Y, Szpirer C, Matsumoto K. Assignments of the genes for rat pituitary adenylate cyclase activating polypeptide (Adcyap1) and its receptor subtypes (Adcyap1r1, Adcyap1r2, and Adcyap1r3). Cytogenet Cell Genet. 1995;71:193-196.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Okazaki K, Itoh Y, Ogi K, Ohkubo S, Onda H. Characterization of murine PACAP mRNA. Peptides. 1995;16:1295-1299.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Nussdorfer GG, Malendowicz LK. Role of VIP, PACAP, and related peptides in the regulation of the hypothalamo-pituitary-adrenal axis. Peptides. 1998;19:1443-1467.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Wang HY, Jiang XM, Ganea D. The neuropeptides VIP and PACAP inhibit IL-2 transcription by decreasing c-Jun and increasing JunB expression in T cells. J Neuroimmunol. 2000;104:68-78.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Voice JK, Dorsam G, Chan RC, Grinninger C, Kong Y, Goetzl EJ. Immunoeffector and immunoregulatory activities of vasoactive intestinal peptide. Regul Pept. 2002;109:199-208.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Delgado M, Leceta J, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide promote in vivo generation of memory Th2 cells. FASEB J. 2002;16:1844-1846.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Calvo JR, Pozo D, Guerrero JM. Functional and molecular characterization of VIP receptors and signal transduction in human and rodent immune systems. Adv Neuroimmunol. 1996;6:39-47.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Goetzl EJ, Pankhaniya RR, Gaufo GO, Mu Y, Xia M, Sreedharan SP. Selectivity of effects of vasoactive intestinal peptide on macrophages and lymphocytes in compartmental immune responses. Ann N Y Acad Sci. 1998;840:540-550.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med. 2001;7:563-568.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Williams RO. Therapeutic effect of vasoactive intestinal peptide in collagen-induced arthritis. Arthritis Rheum. 2002;46:271-273.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Kang H, Byun DG, Kim JW. Effects of substance P and vasoactive intestinal peptide on interferon-gamma and interleukin-4 production in severe atopic dermatitis. Ann Allergy Asthma Immunol. 2000;85:227-232.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Abad C, Martinez C, Leceta J, Juarranz MG, Delgado M, Gomariz RP. Pituitary adenylate-cyclase-activating polypeptide expression in the immune system. Neuroimmunomodulation. 2002;10:177-186.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Fernandez-Martin A, Gonzalez-Rey E, Chorny A, Martin J, Pozo D, Ganea D, Delgado M. VIP prevents experimental multiple sclerosis by downregulating both inflammatory and autoimmune components of the disease. Ann N Y Acad Sci. 2006;1070:276-281.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Moody TW, Hill JM, Jensen RT. VIP as a trophic factor in the CNS and cancer cells. Peptides. 2003;24:163-177.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Pozo D, Anderson P, Gonzalez-Rey E. Induction of alloantigen-specific human T regulatory cells by vasoactive intestinal peptide. J Immunol. 2009;183:4346-4359.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Laburthe M, Couvineau A, Tan V. Class II G protein-coupled receptors for VIP and PACAP: structure, models of activation and pharmacology. Peptides. 2007;28:1631-1639.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Ceraudo E, Murail S, Tan YV, Lacapère JJ, Neumann JM, Couvineau A, Laburthe M. The vasoactive intestinal peptide (VIP) alpha-Helix up to C terminus interacts with the N-terminal ectodomain of the human VIP/Pituitary adenylate cyclase-activating peptide 1 receptor: photoaffinity, molecular modeling, and dynamics. Mol Endocrinol. 2008;22:147-155.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Sreedharan SP, Huang JX, Cheung MC, Goetzl EJ. Structure, expression, and chromosomal localization of the type I human vasoactive intestinal peptide receptor gene. Proc Natl Acad Sci U S A. 1995;92:2939-2943.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Ishihara T, Shigemoto R, Mori K, Takahashi K, Nagata S. Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide. Neuron. 1992;8:811-819.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Usdin TB, Bonner TI, Mezey E. Two receptors for vasoactive intestinal polypeptide with similar specificity and complementary distributions. Endocrinology. 1994;135:2662-2680.  [PubMed]  [DOI]  [Cited in This Article: ]
42.  Goursaud S, Pineau N, Becq-Giraudon L, Gressens P, Muller JM, Janet T. Human H9 cells proliferation is differently controlled by vasoactive intestinal peptide or peptide histidine methionine: implication of a GTP-insensitive form of VPAC1 receptor. J Neuroimmunol. 2005;158:94-105.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  El Zein N, Badran B, Sariban E. VIP differentially activates beta2 integrins, CR1, and matrix metalloproteinase-9 in human monocytes through cAMP/PKA, EPAC, and PI-3K signaling pathways via VIP receptor type 1 and FPRL1. J Leukoc Biol. 2008;83:972-981.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Delgado M, Munoz-Elias EJ, Kan Y, Gozes I, Fridkin M, Brenneman DE, Gomariz RP, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit tumor necrosis factor alpha transcriptional activation by regulating nuclear factor-kB and cAMP response element-binding protein/c-Jun. J Biol Chem. 1998;273:31427-31436.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Lara-Marquez M, O'Dorisio M, O'Dorisio T, Shah M, Karacay B. Selective gene expression and activation-dependent regulation of vasoactive intestinal peptide receptor type 1 and type 2 in human T cells. J Immunol. 2001;166:2522-2530.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Vomhof-DeKrey EE, Dorsam GP. Stimulatory and suppressive signal transduction regulates vasoactive intestinal peptide receptor-1 (VPAC-1) in primary mouse CD4 T cells. Brain Behav Immun. 2008;22:1024-1031.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Vomhof-DeKrey EE, Hermann RJ, Palmer MF, Benton KD, Sandy AR, Dorsam ST, Dorsam GP. TCR signaling and environment affect vasoactive intestinal peptide receptor-1 (VPAC-1) expression in primary mouse CD4 T cells. Brain Behav Immun. 2008;22:1032-1040.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Dorsam ST, Vomhof-Dekrey E, Hermann RJ, Haring JS, Van der Steen T, Wilkerson E, Boskovic G, Denvir J, Dementieva Y, Primerano D. Identification of the early VIP-regulated transcriptome and its associated, interactome in resting and activated murine CD4 T cells. Mol Immunol. 2010;47:1181-1194.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Yadav M, Goetzl EJ. Vasoactive intestinal peptide-mediated Th17 differentiation: an expanding spectrum of vasoactive intestinal peptide effects in immunity and autoimmunity. Ann N Y Acad Sci. 2008;1144:83-89.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Vomhof-Dekrey EE, Haring JS, Dorsam GP. Vasoactive intestinal peptide receptor 1 is downregulated during expansion of antigen-specific CD8 T cells following primary and secondary Listeria monocytogenes infections. J Neuroimmunol. 2011;234:40-48.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Benton KD, Hermann RJ, Vomhof-DeKrey EE, Haring JS, Van der Steen T, Smith J, Dovat S, Dorsam GP. A transcriptionally permissive epigenetic landscape at the vasoactive intestinal peptide receptor-1 promoter suggests a euchromatin nuclear position in murine CD4 T cells. Regul Pept. 2009;158:68-76.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Anderson P, Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Mol Cell Biol. 2010;30:2537-2551.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Sharma V, Delgado M, Ganea D. Granzyme B, a new player in activation-induced cell death, is down-regulated by vasoactive intestinal peptide in Th2 but not Th1 effectors. J Immunol. 2006;176:97-110.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Rameshwar P, Gascon P, Oh HS, Denny TN, Zhu G, Ganea D. Vasoactive intestinal peptide (VIP) inhibits the proliferation of bone marrow progenitors through the VPAC1 receptor. Exp Hematol. 2002;30:1001-1009.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Kawakami M, Kimura T, Kishimoto Y, Tatekawa T, Baba Y, Nishizaki T, Matsuzaki N, Taniguchi Y, Yoshihara S, Ikegame K. Preferential expression of the vasoactive intestinal peptide (VIP) receptor VPAC1 in human cord blood-derived CD34+CD38- cells: possible role of VIP as a growth-promoting factor for hematopoietic stem/progenitor cells. Leukemia. 2004;18:912-921.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Johnson MC, McCormack RJ, Delgado M, Martinez C, Ganea D. Murine T-lymphocytes express vasoactive intestinal peptide receptor 1 (VIP-R1) mRNA. J Neuroimmunol. 1996;68:109-119.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Xin Z, Jiang X, Wang HY, Denny TN, Dittel BN, Ganea D. Effect of vasoactive intestinal peptide (VIP) on cytokine production and expression of VIP receptors in thymocyte subsets. Regul Pept. 1997;72:41-54.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Lara-Marquez ML, O'Dorisio MS, Karacay B. Vasoactive intestinal peptide (VIP) receptor type 2 (VPAC2) is the predominant receptor expressed in human thymocytes. Ann N Y Acad Sci. 2000;921:45-54.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Pankhaniya R, Jabrane-Ferrat N, Gaufo GO, Sreedharan SP, Dazin P, Kaye J, Goetzl EJ. Vasoactive intestinal peptide enhancement of antigen-induced differentiation of a cultured line of mouse thymocytes. FASEB J. 1998;12:119-127.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Porritt HE, Rumfelt LL, Tabrizifard S, Schmitt TM, Zúñiga-Pflücker JC, Petrie HT. Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity. 2004;20:735-745.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Voice JK, Dorsam G, Lee H, Kong Y, Goetzl EJ. Allergic diathesis in transgenic mice with constitutive T cell expression of inducible vasoactive intestinal peptide receptor. FASEB J. 2001;15:2489-2496.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Delgado M, Garrido E, Martinez C, Leceta J, Gomariz RP. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptides (PACAP27) and PACAP38) protect CD4+CD8+ thymocytes from glucocorticoid-induced apoptosis. Blood. 1996;87:5152-5161.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Goetzl EJ, Voice JK, Shen S, Dorsam G, Kong Y, West KM, Morrison CF, Harmar AJ. Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC(2) receptor for vasoactive intestinal peptide. Proc Natl Acad Sci U S A. 2001;98:13854-13859.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Colwell CS, Michel S, Itri J, Rodriguez W, Tam J, Lelievre V, Hu Z, Liu X, Waschek JA. Disrupted circadian rhythms in VIP- and PHI-deficient mice. Am J Physiol Regul Integr Comp Physiol. 2003;285:R939-R949.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Hamidi SA, Szema AM, Lyubsky S, Dickman KG, Degene A, Mathew SM, Waschek JA, Said SI. Clues to VIP function from knockout mice. Ann N Y Acad Sci. 2006;1070:5-9.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Szema AM, Hamidi SA, Lyubsky S, Dickman KG, Mathew S, Abdel-Razek T, Chen JJ, Waschek JA, Said SI. Mice lacking the VIP gene show airway hyperresponsiveness and airway inflammation, partially reversible by VIP. Am J Physiol Lung Cell Mol Physiol. 2006;291:L880-L886.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, Jiang YP, Chen JJ, Waschek JA, Kort S. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation. 2007;115:1260-1268.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J. 2008;31:135-139.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Lelievre V, Favrais G, Abad C, Adle-Biassette H, Lu Y, Germano PM, Cheung-Lau G, Pisegna JR, Gressens P, Lawson G. Gastrointestinal dysfunction in mice with a targeted mutation in the gene encoding vasoactive intestinal polypeptide: a model for the study of intestinal ileus and Hirschsprung's disease. Peptides. 2007;28:1688-1699.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Pincus DW, DiCicco-Bloom EM, Black IB. Vasoactive intestinal peptide regulation of neuroblast mitosis and survival: role of cAMP. Brain Res. 1990;514:355-357.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Pincus DW, DiCicco-Bloom EM, Black IB. Vasoactive intestinal peptide regulates mitosis, differentiation and survival of cultured sympathetic neuroblasts. Nature. 1990;343:564-567.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Bokaei PB, Ma XZ, Byczynski B, Keller J, Sakac D, Fahim S, Branch DR. Identification and characterization of five-transmembrane isoforms of human vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide receptors. Genomics. 2006;88:791-800.  [PubMed]  [DOI]  [Cited in This Article: ]
73.  Bresson-Bépoldin L, Jacquot MC, Schlegel W, Rawlings SR. Multiple splice variants of the pituitary adenylate cyclase-activating polypeptide type 1 receptor detected by RT-PCR in single rat pituitary cells. J Mol Endocrinol. 1998;21:109-120.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Schulz S, Röcken C, Mawrin C, Weise W, Höllt V, Schulz S. Immunocytochemical identification of VPAC1, VPAC2, and PAC1 receptors in normal and neoplastic human tissues with subtype-specific antibodies. Clin Cancer Res. 2004;10:8235-8242.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Reubi JC, Läderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA. Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res. 2000;60:3105-3112.  [PubMed]  [DOI]  [Cited in This Article: ]
76.  Moody TW, Walters J, Casibang M, Zia F, Gozes Y. VPAC1 receptors and lung cancer. Ann N Y Acad Sci. 2000;921:26-32.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  O'Dorisio MS, Shannon BT, Mulne AF, Zwick D, Grossman NJ, Ruymann FB. Vasoactive intestinal peptide receptor expression on human lymphoblasts. Am J Pediatr Hematol Oncol. 1992;14:144-150.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Xia M, Sreedharan SP, Goetzl EJ. Predominant expression of type II vasoactive intestinal peptide receptors by human T lymphoblastoma cells: transduction of both Ca2+ and cyclic AMP signals. J Clin Immunol. 1996;16:21-30.  [PubMed]  [DOI]  [Cited in This Article: ]
79.  Beed EA, O'Dorisio MS, O'Dorisio TM, Gaginella TS. Demonstration of a functional receptor for vasoactive intestinal polypeptide on Molt 4b T lymphoblasts. Regul Pept. 1983;6:1-12.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Finch RJ, Sreedharan SP, Goetzl EJ. High-affinity receptors for vasoactive intestinal peptide on human myeloma cells. J Immunol. 1989;142:1977-1981.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Xia M, Gaufo GO, Wang Q, Sreedharan SP, Goetzl EJ. Transduction of specific inhibition of HuT 78 human T cell chemotaxis by type I vasoactive intestinal peptide receptors. J Immunol. 1996;157:1132-1138.  [PubMed]  [DOI]  [Cited in This Article: ]
82.  Waschek JA, Bravo DT, Richards ML. High levels of vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor mRNA expression in primary and tumor lymphoid cells. Regul Pept. 1995;60:149-157.  [PubMed]  [DOI]  [Cited in This Article: ]
83.  Abello J, Damien C, De Neef P, Tastenoy M, Hooghe R, Robberecht P, Christophe J. Properties of vasoactive-intestinal-peptide receptors and beta-adrenoceptors in the murine radiation leukemia-virus-induced lymphoma cell line BL/VL3. Eur J Biochem. 1989;183:263-267.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Abello J, Damien C, Robberecht P, Hooghe R, Vandermeers A, Vandermeers-Piret MC, Christophe J. Homologous and heterologous regulation of the helodermin/vasoactive-intestinal-peptide response in the murine radiation leukemia-virus-induced lymphoma cell line BL/VL3. Eur J Biochem. 1989;183:269-274.  [PubMed]  [DOI]  [Cited in This Article: ]
85.  Scupoli MT, Vinante F, Krampera M, Vincenzi C, Nadali G, Zampieri F, Ritter MA, Eren E, Santini F, Pizzolo G. Thymic epithelial cells promote survival of human T-cell acute lymphoblastic leukemia blasts: the role of interleukin-7. Haematologica. 2003;88:1229-1237.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Georgopoulos K. Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nat Rev Immunol. 2002;2:162-174.  [PubMed]  [DOI]  [Cited in This Article: ]
87.  Kaufmann C, Yoshida T, Perotti EA, Landhuis E, Wu P, Georgopoulos K. A complex network of regulatory elements in Ikaros and their activity during hemo-lymphopoiesis. EMBO J. 2003;22:2211-2223.  [PubMed]  [DOI]  [Cited in This Article: ]
88.  Papathanasiou P, Perkins AC, Cobb BS, Ferrini R, Sridharan R, Hoyne GF, Nelms KA, Smale ST, Goodnow CC. Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor. Immunity. 2003;19:131-144.  [PubMed]  [DOI]  [Cited in This Article: ]
89.  Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol. 1997;15:155-176.  [PubMed]  [DOI]  [Cited in This Article: ]
90.  Sun L, Liu A, Georgopoulos K. Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J. 1996;15:5358-5369.  [PubMed]  [DOI]  [Cited in This Article: ]
91.  Kirstetter P, Thomas M, Dierich A, Kastner P, Chan S. Ikaros is critical for B cell differentiation and function. Eur J Immunol. 2002;32:720-730.  [PubMed]  [DOI]  [Cited in This Article: ]
92.  Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, Bigby M, Georgopoulos K. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity. 1996;5:537-549.  [PubMed]  [DOI]  [Cited in This Article: ]
93.  Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, Sharpe A. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994;79:143-156.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995;83:289-299.  [PubMed]  [DOI]  [Cited in This Article: ]
95.  Nakayama H, Ishimaru F, Katayama Y, Nakase K, Sezaki N, Takenaka K, Shinagawa K, Ikeda K, Niiya K, Harada M. Ikaros expression in human hematopoietic lineages. Exp Hematol. 2000;28:1232-1238.  [PubMed]  [DOI]  [Cited in This Article: ]
96.  Bellavia D, Mecarozzi M, Campese AF, Grazioli P, Gulino A, Screpanti I. Notch and Ikaros: not only converging players in T cell leukemia. Cell Cycle. 2007;6:2730-2734.  [PubMed]  [DOI]  [Cited in This Article: ]
97.  Iacobucci I, Lonetti A, Cilloni D, Messa F, Ferrari A, Zuntini R, Ferrari S, Ottaviani E, Arruga F, Paolini S. Identification of different Ikaros cDNA transcripts in Philadelphia-positive adult acute lymphoblastic leukemia by a high-throughput capillary electrophoresis sizing method. Haematologica. 2008;93:1814-1821.  [PubMed]  [DOI]  [Cited in This Article: ]
98.  Iacobucci I, Lonetti A, Messa F, Cilloni D, Arruga F, Ottaviani E, Paolini S, Papayannidis C, Piccaluga PP, Giannoulia P. Expression of spliced oncogenic Ikaros isoforms in Philadelphia-positive acute lymphoblastic leukemia patients treated with tyrosine kinase inhibitors: implications for a new mechanism of resistance. Blood. 2008;112:3847-3855.  [PubMed]  [DOI]  [Cited in This Article: ]
99.  Meleshko AN, Movchan LV, Belevtsev MV, Savitskaja TV. Relative expression of different Ikaros isoforms in childhood acute leukemia. Blood Cells Mol Dis. 2008;41:278-283.  [PubMed]  [DOI]  [Cited in This Article: ]
100.  Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, Ma J, Liu W, Cheng C, Schulman BA. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470-480.  [PubMed]  [DOI]  [Cited in This Article: ]
101.  Marçais A, Jeannet R, Hernandez L, Soulier J, Sigaux F, Chan S, Kastner P. Genetic inactivation of Ikaros is a rare event in human T-ALL. Leuk Res. 2010;34:426-429.  [PubMed]  [DOI]  [Cited in This Article: ]
102.  Winandy S, Wu L, Wang JH, Georgopoulos K. Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros. J Exp Med. 1999;190:1039-1048.  [PubMed]  [DOI]  [Cited in This Article: ]
103.  Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999;10:345-355.  [PubMed]  [DOI]  [Cited in This Article: ]
104.  Koipally J, Georgopoulos K. Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression. J Biol Chem. 2002;277:23143-23149.  [PubMed]  [DOI]  [Cited in This Article: ]
105.  Koipally J, Renold A, Kim J, Georgopoulos K. Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. EMBO J. 1999;18:3090-3100.  [PubMed]  [DOI]  [Cited in This Article: ]
106.  Koipally J, Georgopoulos K. Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity. J Biol Chem. 2000;275:19594-19602.  [PubMed]  [DOI]  [Cited in This Article: ]
107.  Molnár A, Georgopoulos K. The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol. 1994;14:8292-8303.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Klug CA, Morrison SJ, Masek M, Hahm K, Smale ST, Weissman IL. Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci U S A. 1998;95:657-662.  [PubMed]  [DOI]  [Cited in This Article: ]
109.  Ronni T, Payne KJ, Ho S, Bradley MN, Dorsam G, Dovat S. Human Ikaros function in activated T cells is regulated by coordinated expression of its largest isoforms. J Biol Chem. 2007;282:2538-2547.  [PubMed]  [DOI]  [Cited in This Article: ]
110.  Gurel Z, Ronni T, Ho S, Kuchar J, Payne KJ, Turk CW, Dovat S. Recruitment of ikaros to pericentromeric heterochromatin is regulated by phosphorylation. J Biol Chem. 2008;283:8291-8300.  [PubMed]  [DOI]  [Cited in This Article: ]
111.  Popescu M, Gurel Z, Ronni T, Song C, Hung KY, Payne KJ, Dovat S. Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. J Biol Chem. 2009;284:13869-13880.  [PubMed]  [DOI]  [Cited in This Article: ]
112.  Molnár A, Wu P, Largespada DA, Vortkamp A, Scherer S, Copeland NG, Jenkins NA, Bruns G, Georgopoulos K. The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. J Immunol. 1996;156:585-592.  [PubMed]  [DOI]  [Cited in This Article: ]
113.  Dorsam G, Goetzl EJ. Vasoactive intestinal peptide receptor-1 (VPAC-1) is a novel gene target of the hemolymphopoietic transcription factor Ikaros. J Biol Chem. 2002;277:13488-13493.  [PubMed]  [DOI]  [Cited in This Article: ]
114.  Kleinmann E, Geimer Le Lay AS, Sellars M, Kastner P, Chan S. Ikaros represses the transcriptional response to Notch signaling in T-cell development. Mol Cell Biol. 2008;28:7465-7475.  [PubMed]  [DOI]  [Cited in This Article: ]
115.  Reubi JC. In vitro evaluation of VIP/PACAP receptors in healthy and diseased human tissues. Clinical implications. Ann N Y Acad Sci. 2000;921:1-25.  [PubMed]  [DOI]  [Cited in This Article: ]
116.  Fernández-Martínez AB, Bajo AM, Valdehita A, Isabel Arenas M, Sánchez-Chapado M, Carmena MJ, Prieto JC. Multifunctional role of VIP in prostate cancer progression in a xenograft model: suppression by curcumin and COX-2 inhibitor NS-398. Peptides. 2009;30:2357-2364.  [PubMed]  [DOI]  [Cited in This Article: ]
117.  Ortner A, Wernig K, Kaisler R, Edetsberger M, Hajos F, Köhler G, Mosgoeller W, Zimmer A. VPAC receptor mediated tumor cell targeting by protamine based nanoparticles. J Drug Target. 2010;18:457-467.  [PubMed]  [DOI]  [Cited in This Article: ]
118.  Moody TW, Gozes I. Vasoactive intestinal peptide receptors: a molecular target in breast and lung cancer. Curr Pharm Des. 2007;13:1099-1104.  [PubMed]  [DOI]  [Cited in This Article: ]
119.  Reubi JC, Körner M, Waser B, Mazzucchelli L, Guillou L. High expression of peptide receptors as a novel target in gastrointestinal stromal tumours. Eur J Nucl Med Mol Imaging. 2004;31:803-810.  [PubMed]  [DOI]  [Cited in This Article: ]
120.  Valdehita A, Bajo AM, Schally AV, Varga JL, Carmena MJ, Prieto JC. Vasoactive intestinal peptide (VIP) induces transactivation of EGFR and HER2 in human breast cancer cells. Mol Cell Endocrinol. 2009;302:41-48.  [PubMed]  [DOI]  [Cited in This Article: ]
121.  Falktoft B, Georg B, Fahrenkrug J. Calmodulin interacts with PAC1 and VPAC2 receptors and regulates PACAP-induced FOS expression in human neuroblastoma cells. Neuropeptides. 2009;43:53-61.  [PubMed]  [DOI]  [Cited in This Article: ]
122.  Gutiérrez-Cañas I, Rodríguez-Henche N, Bolaños O, Carmena MJ, Prieto JC, Juarranz MG. VIP and PACAP are autocrine factors that protect the androgen-independent prostate cancer cell line PC-3 from apoptosis induced by serum withdrawal. Br J Pharmacol. 2003;139:1050-1058.  [PubMed]  [DOI]  [Cited in This Article: ]
123.  Balster DA, O'Dorisio MS, Albers AR, Park SK, Qualman SJ. Suppression of tumorigenicity in neuroblastoma cells by upregulation of human vasoactive intestinal peptide receptor type 1. Regul Pept. 2002;109:155-165.  [PubMed]  [DOI]  [Cited in This Article: ]
124.  Juarranz MG, Bolaños O, Gutiérrez-Cañas I, Lerner EA, Robberecht P, Carmena MJ, Prieto JC, Rodríguez-Henche N. Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors. Cell Signal. 2001;13:887-894.  [PubMed]  [DOI]  [Cited in This Article: ]
125.  Cochaud S, Chevrier L, Meunier AC, Brillet T, Chadéneau C, Muller JM. The vasoactive intestinal peptide-receptor system is involved in human glioblastoma cell migration. Neuropeptides. 2010;44:373-383.  [PubMed]  [DOI]  [Cited in This Article: ]
126.  Hayez N, Harfi I, Lema-Kisoka R, Svoboda M, Corazza F, Sariban E. The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) modulate several biochemical pathways in human leukemic myeloid cells. J Neuroimmunol. 2004;149:167-181.  [PubMed]  [DOI]  [Cited in This Article: ]
127.  Valdehita A, Carmena MJ, Collado B, Prieto JC, Bajo AM. Vasoactive intestinal peptide (VIP) increases vascular endothelial growth factor (VEGF) expression and secretion in human breast cancer cells. Regul Pept. 2007;144:101-108.  [PubMed]  [DOI]  [Cited in This Article: ]
128.  Collado B, Sánchez-Chapado M, Prieto JC, Carmena MJ. Hypoxia regulation of expression and angiogenic effects of vasoactive intestinal peptide (VIP) and VIP receptors in LNCaP prostate cancer cells. Mol Cell Endocrinol. 2006;249:116-122.  [PubMed]  [DOI]  [Cited in This Article: ]
129.  Summers MA, O'Dorisio MS, Cox MO, Lara-Marquez M, Goetzl EJ. A lymphocyte-generated fragment of vasoactive intestinal peptide with VPAC1 agonist activity and VPAC2 antagonist effects. J Pharmacol Exp Ther. 2003;306:638-645.  [PubMed]  [DOI]  [Cited in This Article: ]
130.  Robberecht P, Abello J, Damien C, de Neef P, Vervisch E, Hooghe R, Christophe J. Variable stimulation of adenylate cyclase activity by vasoactive intestinal-like peptides and beta-adrenergic agonists in murine T cell lymphomas of immature, helper, and cytotoxic types. Immunobiology. 1989;179:422-431.  [PubMed]  [DOI]  [Cited in This Article: ]