• 5-Fluorouracil resistance
• Colorectal cancer
• Migration
• NEK2
• Proliferation
• Wnt/β-catenin signaling pathway

• 201702220 Henan Province medical science and technology research project
• 201702246 Henan Province medical science and technology research project

• Male
• Humans
• Infertility, Male/genetics
• Infertility, Male/diagnosis
• Infertility, Male/therapy
• Infertility, Male/metabolism
• Spermatozoa/metabolism
• RNA/genetics
• Spermatogenesis/genetics
• Sperm Retrieval
• Reproductive Techniques, Assisted

• inflammation
• computational biology and bioinformatics
• functional genomics
• reproductive biology

• Female
• Pregnancy
• Placenta/metabolism
• Placenta/immunology
• Animals
• Fetus/immunology
• Fetus/metabolism
• Lung/immunology
• Lung/metabolism
• Lipopolysaccharides
• Liver/metabolism
• Liver/immunology
• Docosahexaenoic Acids/metabolism
• Suppressor of Cytokine Signaling 3 Protein/metabolism
• Suppressor of Cytokine Signaling 3 Protein/genetics
• Mice
• Inflammation/immunology
• Inflammation/metabolism
• Mice, Inbred C57BL
• Adaptation, Physiological/immunology
• Fetal Development/immunology
• Maternal-Fetal Exchange/immunology
• Interleukin-6/metabolism
• Interleukin-6/immunology

• MAPK signaling
• apoptosis
• blood testis barrier
• low-fertile bulls
• oxidative phosphorylation
• spermatogenesis

• Kupffer cell
• Proliferation
• Simulated microgravity
• Transcriptome sequencing

• Humans
• Transcriptome
• Weightlessness
• Kupffer Cells
• Cell Proliferation
• Weightlessness Simulation
• Enhancer of Zeste Homolog 2 Protein
• Proto-Oncogene Proteins
• Adaptor Proteins, Signal Transducing
• LIM Domain Proteins/genetics

• Cyclophilin A
• Nek2
• centrosome
• midbody
• mitosis
• phosphorylation

• Phosphorylation
• Protein Serine-Threonine Kinases/metabolism
• Cyclophilin A
• Peptidylprolyl Isomerase/metabolism
• NIMA-Related Kinases/metabolism
• Mitosis
• Centrosome/metabolism
• Serine/metabolism
• Cell Cycle Proteins/metabolism

• Wellcome Trust

• Cdc5
• MTOCs
• PLK1
• cell cycle
• centrosomes
• spindle pole bodies

• Canadian Institutes of Health Research

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype. Poor prognosis in TNBC is partly due to lack of efficacious targeted therapy and high propensity to metastasize. Dysregulation of alternative splicing has recently emerged as a trait of TNBC, suggesting that unveiling the molecular mechanisms underlying its regulation could uncover new druggable cancer vulnerabilities. The oncogenic kinase NEK2 is significantly upregulated in TNBC and contributes to shaping their unique splicing profile. Herein, we found that NEK2 interacts with the RNA binding protein Sam68 in TNBC cells and that NEK2-mediated phosphorylation of Sam68 enhances its splicing activity. Genome-wide transcriptome analyses identified the splicing targets of Sam68 in TNBC cells and revealed a common set of exons that are co-regulated by NEK2. Functional annotation of splicing-regulated genes highlighted cell migration and spreading as biological processes regulated by Sam68. Accordingly, Sam68 depletion reduces TNBC cell migration and invasion, and these effects are potentiated by the concomitant inhibition of NEK2 activity. Our findings indicate that Sam68 and NEK2 functionally cooperate in the regulation of a splicing program that sustains the pro-metastatic features of TNBC cells.

• NEK2
• SAM68
• alternative splicing
• transcriptomics
• triple-negative breast cancer

• Chemoradiotherapy
• Combined therapy
• Immunotherapy
• NEK2
• Targeted therapy

• Chemoradiotherapy
• Humans
• Immunotherapy
• NIMA-Related Kinases/genetics
• NIMA-Related Kinases/metabolism
• Neoplasms/drug therapy
• Neoplasms/genetics
• Protein Serine-Threonine Kinases/genetics

• CRISPR/Cas9
• behavior
• high mobility group AT-hook 2
• sterility

• Animals
• Epididymis/metabolism
• Epididymis/pathology
• Female
• Growth Disorders/metabolism
• Growth Disorders/pathology
• HMGA2 Protein/genetics
• HMGA2 Protein/metabolism
• Infertility/metabolism
• Infertility/pathology
• Male
• Mice
• Pregnancy
• Rabbits
• Reproduction/genetics
• Testis/metabolism

• R00 HD081204 NICHD NIH HHS
• R01 HD102909 NICHD NIH HHS
• The Hagler Institute for Advanced Study at Texas A&M University (PI L.A.)
• Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health
• National Institutes of Health

• Nek2 PROTACS
• Nek2 in cancer metastasis
• Nek2 inhibitors
• Nek2 kinase review
• Nek2 kinase signaling
• centrosomal kinase
• mitotic kinase
• small molecule inhibitors of Nek2 kinase

• Bone Diseases/drug therapy
• Bone Diseases/enzymology
• Bone Diseases/pathology
• Drug Resistance
• Enzyme Inhibitors/pharmacology
• Humans
• Immune System Diseases/drug therapy
• Immune System Diseases/enzymology
• Immune System Diseases/pathology
• Kidney Diseases/drug therapy
• Kidney Diseases/enzymology
• Kidney Diseases/pathology
• Malaria/drug therapy
• Malaria/enzymology
• Malaria/pathology
• NIMA-Related Kinases/antagonists & inhibitors
• Neoplasm Metastasis
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/pathology

• R15 CA243109 NCI NIH HHS
• 1R15CA243109-01 NIH HHS

• circular RNAs
• idiopathic non-obstructive azoospermia
• microdissection testicular sperm extraction
• seminal plasma

Testicular germ cell tumors (TGCTs) are the most common tumors in adolescent and young men. Recently, genome-wide studies have made it possible to progress in understanding the molecular mechanisms underlying the development of tumors. It is becoming increasingly clear that aberrant regulation of RNA metabolism can drive tumorigenesis and influence chemotherapeutic response. Notably, the expression of non-coding RNAs as well as specific splice variants is deeply deregulated in human cancers. Since these cancer-related RNA species are considered promising diagnostic, prognostic and therapeutic targets, understanding their function in cancer development is becoming a major challenge. Here, we summarize how the different expression of RNA species repertoire, including non-coding RNAs and protein-coding splicing variants, impacts on TGCTs’ onset and progression and sustains therapeutic resistance. Finally, the role of transcription-associated R-loop misregulation in the maintenance of genomic stability in TGCTs is also discussed.

• R-loop
• lncRNA
• rRNA
• sncRNA
• splicing
• testicular germ cell tumor

• Cancer
• Cell cycle
• Cell cycle-directed anti-cancer therapies
• HMGA
• TP53

• Cell Cycle Checkpoints/physiology
• DNA Damage
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Genomic Instability
• HMGA Proteins/genetics
• HMGA Proteins/metabolism
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Signal Transduction
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

Non-obstructive azoospermia (NOA) is a disease related to spermatogenic disorders. Currently, the specific etiological mechanism of NOA is unclear. This study aimed to use integrated bioinformatics to screen biomarkers and pathways involved in NOA and reveal their potential molecular mechanisms.

GSE145467 and GSE108886 gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between NOA tissues and matched obstructive azoospermia (OA) tissues were identified using the GEO2R tool. Common DEGs in the two datasets were screened out by the VennDiagram package. For the functional annotation of common DEGs, DAVID v.6.8 was used to perform Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. In accordance with data collected from the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, a protein–protein interaction (PPI) network was constructed by Cytoscape. Cytohubba in Cytoscape was used to screen the hub genes. Furthermore, the hub genes were validated based on a separate dataset, GSE9210. Finally, potential micro RNAs (miRNAs) of hub genes were predicted by miRWalk 3.0.

A total of 816 common DEGs, including 52 common upregulated and 764 common downregulated genes in two datasets, were screened out. Some of the more important of these pathways, including focal adhesion, PI3K-Akt signaling pathway, cell cycle, oocyte meiosis, AMP-activated protein kinase (AMPK) signaling pathway, FoxO signaling pathway, and Huntington disease, were involved in spermatogenesis. We further identified the top 20 hub genes from the PPI network, including CCNB2, DYNLL2, HMMR, NEK2, KIF15, DLGAP5, NUF2, TTK, PLK4, PTTG1, PBK, CEP55, CDKN3, CDC25C, MCM4, DNAI1, TYMS, PPP2R1B, DNAI2, and DYNLRB2, which were all downregulated genes. In addition, potential miRNAs of hub genes, including hsa-miR-3666, hsa-miR-130b-3p, hsa-miR-15b-5p, hsa-miR-6838-5p, and hsa-miR-195-5p, were screened out.

Taken together, the identification of the above hub genes, miRNAs and pathways will help us better understand the mechanisms associated with NOA, and provide potential biomarkers and therapeutic targets for NOA.

• Non-obstructive azoospermia (NOA)
• biomarkers
• expression profiling data
• functional enrichment analysis
• protein–protein interactions

• HMGA2
• UV radiation
• biomarker
• keratinocytes
• skin cancer

• HMGA1
• microRNA
• seminoma
• testicular germ cell tumor (TGCT)

Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy. A distinctive characteristic of KS is oligozoospermia. Despite multiple studies that have described the natural history of the degenerative process of germ cells in patients with KS, the molecular mechanisms that initiate this process are not well characterized. MicroRNA (miRNA)-mediated post-transcriptional control mechanisms have been increasingly recognized as important regulators of spermatogenesis; however, only a few studies have evaluated the role of miRNAs in the gonadal failure of these patients. Here, we describe a differential expression profile for the miRNAs in testicular tissue samples taken from KS patients. We analysed testicular tissue samples from 4 KS patients and 5 control patients (obstructive azoospermia) through next-generation sequencing, which can provide information about the mechanisms involved in the degeneration of germ cells. A distinctive differential expression profile was identified for 166 miRNAs in the KS patients: 66 were upregulated, and 100 were downregulated. An interactome analysis was performed for 7 of the upregulated and the 20 downregulated miRNAs. The results showed that the target genes are involved in the development, proliferation, and differentiation processes of spermatogenesis, which may explain their role in the development of infertility. This is the first report of a miRNA expression profile generated from testicular tissue samples of KS patients.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. There are two subtypes, fusion gene-positive RMS (FP-RMS) and fusion gene-negative RMS (FN-RMS), depending on the presence of a fusion gene, either PAX3-FOXO1 or PAX7-FOXO1. These fusion genes are thought to be oncogenic drivers of FP-RMS. By contrast, the underlying mechanism of FN-RMS has not been thoroughly investigated. It has recently been shown that HMGA2 is specifically positive in pathological tissue from FN-RMS, but the role of HMGA2 in FN-RMS remains to be clarified.

In this study, we used FN-RMS cell lines to investigate the function of HMGA2. Gene expression, cell growth, cell cycle, myogenic differentiation, tumor formation in vivo, and cell viability under drug treatment were assessed.

We found that HMGA2 was highly expressed in FN-RMS cells compared with FP-RMS cells and that knockdown of HMGA2 in FN-RMS cells inhibited cell growth and induced G1 phase accumulation in the cell cycle and myogenic differentiation. Additionally, we showed using both gain-of-function and loss-of-function assays that HMGA2 was required for tumor formation in vivo. Consistent with these findings, the HMGA2 inhibitor netropsin inhibited the cell growth of FN-RMS.

Our results suggest that HMGA2 has important role in the oncogenicity of FP-RMS and may be a potential therapeutic target in patients with FN-RMS.

• Fusion-negative rhabdomyosarcoma
• HMGA2
• Netropsin

Background: Recent studies have underlined HMGA protein’s key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the HMGA1 transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a—two HMGA1-targeting microRNAs. Methods: HMGA1 mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities. Results: an inverse correlation was found between the expression of miR-26a and Let-7a and HMGA1 expression levels in seminomas samples, suggesting a critical role of these microRNAs in HMGA1 levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2. Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is—at least in part—due to the downregulation of HMGA1-targeting microRNAs.

• HMGA1
• TGCTs
• microRNAs
• seminomas

• Aurora B
• GPR30
• HMGA
• PATZ1
• testicular germ cells tumors

HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they are abundantly expressed during embryogenesis, but are downregulated in the adult differentiated tissues. In the present review, we summarize some aspects of their role during development, also dealing with relevant studies that have shed light on their functioning in cell biology and with emerging possible involvement of HMGA1 and HMGA2 in evolutionary biology.

• AT hook
• EMT
• HMGA1
• HMGA2
• cell cycle
• chromatin remodeling
• development
• differentiation
• evolution
• stemness

• Candidate genes
• Duroc pigs
• Semen traits
• Sperm motility
• Weighted single-step GWAS

• co-expression
• hexaploid
• meiosis
• network
• polyploidization
• wheat

• BB/J007188/1 Biotechnology and Biological Sciences Research Council
• BBS/E/J/00000128 Biotechnology and Biological Sciences Research Council
• BBS/E/J/000PR9788 Biotechnology and Biological Sciences Research Council

• Aurora B
• GPR30
• HMGA
• PATZ1
• Testicular germ cells tumors
• seminomas

• NEK2
• cisplatin-based chemotherapy resistance
• nasopharyngeal carcinoma (NPC)

• Cell Line, Tumor
• Cisplatin/administration & dosage
• Disease-Free Survival
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Enzymologic/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Male
• Middle Aged
• NIMA-Related Kinases/biosynthesis
• Nasopharyngeal Carcinoma/drug therapy
• Nasopharyngeal Carcinoma/enzymology
• Nasopharyngeal Carcinoma/mortality
• Nasopharyngeal Neoplasms/drug therapy
• Nasopharyngeal Neoplasms/enzymology
• Nasopharyngeal Neoplasms/mortality
• Survival Rate
• Xenograft Model Antitumor Assays

• HMGA2
• dwarfism
• gene editing
• organ size
• swine

Signaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function. Two members of the dual-specificity phosphatase (Dusp) family, dusp6 and dusp2, are believed to be negative regulators of the ERK pathway and are expressed in both embryonic and adult zebrafish, but their specific roles in embryogenesis remain to be fully understood.

Using CRISPR/Cas9 genome editing technology, we generated zebrafish lines harboring germ line deletions in dusp6 and dusp2. We do not detect any overt defects in dusp2 mutants, but we find that approximately 50% of offspring from homozygous dusp6 mutants do not proceed through embryonic development. These embryos are fertilized, but are unable to proceed past the first zygotic mitosis and stall at the 1-cell stage for several hours before dying by 10 h post fertilization. We demonstrate that dusp6 is expressed in gonads of both male and female zebrafish, suggesting that loss of dusp6 causes defects in germ cell production. Notably, the 50% of homozygous dusp6 mutants that complete the first cell division appear to progress through embryogenesis normally and give rise to fertile adults.

The fact that offspring of homozygous dusp6 mutants stall prior to activation of the zygotic genome, suggests that loss of dusp6 affects gametogenesis and/or parentally-directed early development. Further, since only approximately 50% of homozygous dusp6 mutants are affected, we postulate that ERK signaling is tightly regulated and that dusp6 is required to keep ERK signaling within a range that is permissive for proper embryogenesis. Lastly, since dusp6 is expressed throughout zebrafish embryogenesis, but dusp6 mutants do not exhibit defects after the first cell division, it is possible that other regulators of the ERK pathway compensate for loss of dusp6 at later stages.

The online version of this article (10.1186/s12861-018-0164-6) contains supplementary material, which is available to authorized users.

• CRISPR
• Dual-specific phosphatase
• ERK signaling
• Germ cell development
• MAP kinase phosphatase
• Zebrafish embryonic patterning

• Glioma
• NIMA-related kinase 2
• Overexpression
• Prognosis
• Tumorigenesis

• Cancer
• NEK2
• centrosome
• inhibitor
• mitosis
• oncogenic

• NEK2
• Pharmacophore
• QSAR
• cancer

High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.

• Colorectal cancer
• HMGA2
• Hsp90

• Kinase
• Phosphoinositide
• Second messenger
• Spermatozoa
• Steroids

• Humans
• Male
• Second Messenger Systems
• Signal Transduction/drug effects
• Spermatozoa/cytology
• Spermatozoa/drug effects
• Spermatozoa/metabolism
• Steroids/pharmacology

The group of postpubertal testicular germ cell tumours encompasses lesions with highly diverse differentiation – seminomas, embryonal carcinomas, yolk sac tumours, teratomas and choriocarcinomas. Heterogeneous differentiation is often present within individual tumours and the correct identification of the components is of clinical relevance. HMGA2 re‐expression has been reported in many tumours, including testicular germ cell tumours. This is the first study investigating HMGA2 expression in a representative group of testicular germ cell tumours with the highly sensitive method of quantitative real‐time PCR as well as with immunohistochemistry. The expression of HMGA2 and HPRT was measured using quantitative real‐time PCR in 59 postpubertal testicular germ cell tumours. Thirty specimens contained only one type of tumour and 29 were mixed neoplasms. With the exception of choriocarcinomas, at least two pure specimens from each subgroup of testicular germ cell tumour were included. In order to validate the quantitative real‐time PCR data and gather information about the localisation of the protein, additional immunohistochemical analysis with an antibody specific for HMGA2 was performed in 23 cases. Expression of HMGA2 in testicular germ cell tumours depended on the histological differentiation. Seminomas and embryonal carcinomas showed no or very little expression, whereas yolk sac tumours strongly expressed HMGA2 at the transcriptome as well as the protein level. In teratomas, the expression varied and in choriocarcinomas the expression was moderate. In part, these results contradict data from previous studies but HMGA2 seems to represent a novel marker to assist pathological subtyping of testicular germ cell tumours. The results indicate a critical role in yolk sac tumours and some forms of teratoma.

• HMGA2
• biomarker
• choriocarcinoma
• embryonal carcinoma
• immunohistochemistry
• qRT‐PCR
• seminoma
• teratoma
• testicular germ cell tumour
• yolk sac tumour

Almost 30 years ago, overexpression of HMGA proteins was associated with malignant phenotype of rat thyroid cells transformed with murine retroviruses. Thereafter, several studies have analyzed HMGA expression in a wide range of human neoplasias. Here, we summarize all these results that, in the large majority of the cases, confirm the association of HMGA overexpression with high malignant phenotype as outlined by chemoresistance, spreading of metastases, and a global poor survival. Even though HMGA proteins’ overexpression indicates a poor prognosis in almost all malignancies, their detection may be particularly useful in determining the prognosis of breast, lung, and colon carcinomas, suggesting for the treatment a more aggressive therapy. In particular, the expression of HMGA2 in lung carcinomas is frequently associated with the presence of metastases. Moreover, recent data revealed that often the cause for the high HMGA proteins levels detected in human malignancies is a deregulated expression of non-coding RNA. Therefore, the HMGA proteins represent tumor markers whose detection can be a valid tool for the diagnosis and prognosis of neoplastic diseases.

• HMGA1
• HMGA2
• cancer marker
• diagnosis
• prognosis

Chromosome instability (CIN) has been identified as a common feature of most human cancers. A number of centrosomal kinases are thought to cause CIN in cancer cells. Part of those centrosomal kinases exhibit elevated expression in a wide variety of tumours and cancer cell lines. Additionally, critical roles in many aspects of cancer cell growth, proliferation, metastasis, and drug resistance have been assigned to some of these centrosomal kinases, such as polo-like kinase 1 (PLk1) and Aurora-A kinase. Recent studies from our group and others revealed that a centrosomal kinase, Never in Mitosis (NIMA) Related Kinase 2A (NEK2A), is frequently upregulated in multiple types of human cancers. Uncontrolled activity of NEK2A activates several oncogenic pathways and ABC transporters, thereby leading to CIN, cancer cell proliferation, metastasis, and enhanced drug resistance. In this paper, we highlight recent findings on the aberrant expression and functional significance of NEK2A in human cancers and emphasize their significance for therapeutic potentials.

Gene expression profile in the development of porcine testes investigates the intricate physiological process in pig testis development and spermatogenesis.

• Biology
• DAMP
• Disease
• HMGB1

• Disease
• HMGB1 Protein/physiology
• Health
• Humans

• R01CA181450 NCI NIH HHS
• UL1 TR000005 NCATS NIH HHS
• R01 CA181450 NCI NIH HHS
• P30 CA047904 NCI NIH HHS
• R01CA160417 NCI NIH HHS
• R01AT005076 NCCIH NIH HHS
• R01GM063075 NIGMS NIH HHS
• R01 GM063075 NIGMS NIH HHS
• P30CA047904 NCI NIH HHS
• R01 AT005076 NCCIH NIH HHS
• R01 CA160417 NCI NIH HHS

Aside from Polo and Aurora, a third but less studied kinase family involved in mitosis regulation is the never in mitosis-gene A (NIMA)-related kinases (Neks). The founding member of this family is the sole member NIMA of Aspergillus nidulans, which is crucial for the initiation of mitosis in that organism. All 11 human Neks have been functionally assigned to one of the three core functions established for this family in mammals: (1) centrioles/mitosis; (2) primary ciliary function/ciliopathies; and (3) DNA damage response (DDR). Recent findings, especially on Nek 1 and 8, showed however, that several Neks participate in parallel in at least two of these contexts: primary ciliary function and DDR. In the core section of this in-depth review, we report the current detailed functional knowledge on each of the 11 Neks. In the discussion, we return to the cross-connections among Neks and point out how our and other groups’ functional and interactomics studies revealed that most Neks interact with protein partners associated with two if not all three of the functional contexts. We then raise the hypothesis that Neks may be the connecting regulatory elements that allow the cell to fine tune and synchronize the cellular events associated with these three core functions. The new and exciting findings on the Nek family open new perspectives and should allow the Neks to finally claim the attention they deserve in the field of kinases and cell cycle biology.

• Cell cycle
• Mitosis
• DNA damage response
• Protein interactions
• Kinases

High mobility group (HMG) proteins are the most abundant non-histone chromatin associated proteins. HMG proteins bind to DNA and nucleosome and alter the structure of chromatin locally and globally. Accessibility to DNA within chromatin is a central factor that affects DNA-dependent nuclear processes, such as transcription, replication, recombination, and repair. HMG proteins associate with different multi-protein complexes to regulate these processes by mediating accessibility to DNA. HMG proteins can be subdivided into three families: HMGA, HMGB, and HMGN. In this review, we will focus on recent advances in understanding the function of HMGA family members, specifically their role in gene transcription regulation during development and cancer.

• HMGA
• chromatin structure
• development and cancer
• transcription

• Alternative Splicing
• Apoptosis
• Cell Line, Tumor
• Cell Nucleus/enzymology
• Cell Survival
• Humans
• NIMA-Related Kinases
• Neoplasms/enzymology
• Nuclear Proteins/metabolism
• Protein Serine-Threonine Kinases/analysis
• Protein Serine-Threonine Kinases/metabolism
• RNA-Binding Proteins/metabolism
• Serine-Arginine Splicing Factors
• bcl-X Protein/genetics

• Aurora-B
• GPR30
• HMGA
• PATZ1
• Seminomas
• Testicular germ-cell tumors