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Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, Shi M, Shi W, Xie X, Di C. Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis 2023; 14:244. [PMID: 37024471 PMCID: PMC10079974 DOI: 10.1038/s41419-023-05763-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023]
Abstract
Cyclin D1 (CCND1), a crucial mediator of cell cycle progression, possesses many mutation types with different mutation frequencies in human cancers. The G870A mutation is the most common mutation in CCND1, which produces two isoforms: full-length CCND1a and divergent C-terminal CCND1b. The dysregulation of the CCND1 isoforms is associated with multiple human cancers. Exploring the molecular mechanism of CCND1 isoforms has offer new insight for cancer treatment. On this basis, the alterations of CCND1 gene are described, including amplification, overexpression, and mutation, especially the G870A mutation. Subsequently, we review the characteristics of CCND1 isoforms caused by G870A mutation. Additionally, we summarize cis-regulatory elements, trans-acting factors, and the splice mutation involved in splicing regulation of CCND1. Furthermore, we highlight the function of CCND1 isoforms in cell cycle, invasion, and metastasis in cancers. Importantly, the clinical role of CCND1 isoforms is also discussed, particularly concerning prognosis, chemotherapy, and radiotherapy. Last, emphasis is given to the corrective strategies that modulate the cancerous CCND1 isoforms. Thus, it is highlighting significance of aberrant isoforms of CCND1 as targets for cancer therapy.
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Affiliation(s)
- Jing Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
| | - Wei Su
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Taotao Zhang
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Shasha Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Huiwen Lei
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Fengdie Ma
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Maoning Shi
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Wenjing Shi
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Xiaodong Xie
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China.
| | - Cuixia Di
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China.
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Wang J, Zhang J, Ma Q, Zhang S, Ma F, Su W, Zhang T, Xie X, Di C. Influence of cyclin D1 splicing variants expression on breast cancer chemoresistance via CDK4/CyclinD1-pRB-E2F1 pathway. J Cell Mol Med 2023; 27:991-1005. [PMID: 36915230 PMCID: PMC10064037 DOI: 10.1111/jcmm.17716] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 02/23/2023] [Accepted: 02/25/2023] [Indexed: 03/16/2023] Open
Abstract
Cyclin D1 (CCND1), a mediator of cell cycle control, has a G870A polymorphism which results in the formation of two splicing variants: full-length CCND1 (CCND1a) and C-terminally truncated CCND1 species (CCND1b). However, the role of CCND1a and CCND1b variants in cancer chemoresistance remains unknown. Therefore, this study aimed to explore the molecular mechanism of alternative splicing of CCND1 in breast cancer (BC) chemoresistance. To address the contribution of G870A polymorphism to the production of CCND1 variants in BC chemoresistance, we sequenced the G870A polymorphism and analysed the expressions of CCND1a and CCND1b in MCF-7 and MCF-7/ADM cells. In comparison with MCF-7 cells, MCF-7/ADM cells with the A allele could enhance alternative splicing with the increase of SC-35, upregulate the ratio of CCND1b/a at both mRNA and protein levels, and activate the CDK4/CyclinD1-pRB-E2F1 pathway. Furthermore, CCND1b expression and the downstream signalling pathway were analysed through Western blotting and cell cycle in MCF-7/ADM cells with knockdown of CCND1b. Knockdown of CCND1b downregulated the ratio of CCND1b/a, demoted cell proliferation, decelerated cell cycle progression, inhibited the CDK4/CyclinD1-pRB-E2F1 pathway and thereby decreased the chemoresistance of MCF-7/ADM cells. Finally, CCND1 G870A polymorphism, the alternative splicing of CCDN1 was detected through Sequenom Mass ARRAY platform, Sanger sequencing, semi-quantitative RT-PCR, Western blotting and immunohistochemistry in clinical BC specimens. The increase of the ratio of CCND1b/a caused by G870A polymorphism was involved in BC chemoresistance. Thus, these findings revealed that CCND1b/a ratio caused by the polymorphism is involved in BC chemoresistance via CDK4/CyclinD1-pRB-E2F1 pathway.
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Affiliation(s)
- Jing Wang
- School of Basic Medical SciencesLanzhou UniversityLanzhouChina
- Bio‐Medical Research Center, Institute of Modern PhysicsChinese Academy of SciencesLanzhouChina
| | - Jiaxin Zhang
- School of Biological and Pharmaceutical EngineeringLanzhou Jiaotong UniversityLanzhouChina
| | - Qinglong Ma
- School of Basic Medical SciencesLanzhou UniversityLanzhouChina
| | - Shasha Zhang
- School of Basic Medical SciencesLanzhou UniversityLanzhouChina
| | - Fengdie Ma
- School of Basic Medical SciencesLanzhou UniversityLanzhouChina
| | - Wei Su
- Bio‐Medical Research Center, Institute of Modern PhysicsChinese Academy of SciencesLanzhouChina
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of SciencesLanzhouChina
| | - Taotao Zhang
- Bio‐Medical Research Center, Institute of Modern PhysicsChinese Academy of SciencesLanzhouChina
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of SciencesLanzhouChina
| | - Xiaodong Xie
- School of Basic Medical SciencesLanzhou UniversityLanzhouChina
| | - Cuixia Di
- Bio‐Medical Research Center, Institute of Modern PhysicsChinese Academy of SciencesLanzhouChina
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of SciencesLanzhouChina
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Tzani I, Monger C, Motheramgari K, Gallagher C, Hagan R, Kelly P, Costello A, Meiller J, Floris P, Zhang L, Clynes M, Bones J, Barron N, Clarke C. Subphysiological temperature induces pervasive alternative splicing in Chinese hamster ovary cells. Biotechnol Bioeng 2020; 117:2489-2503. [DOI: 10.1002/bit.27365] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 04/01/2020] [Accepted: 04/26/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Ioanna Tzani
- National Institute for Bioprocessing Research and Training Dublin Ireland
| | - Craig Monger
- National Institute for Bioprocessing Research and Training Dublin Ireland
| | - Krishna Motheramgari
- National Institute for Bioprocessing Research and Training Dublin Ireland
- National Institute for Cellular BiotechnologyDublin City University Glasnevin Dublin Ireland
| | - Clair Gallagher
- National Institute for Cellular BiotechnologyDublin City University Glasnevin Dublin Ireland
| | - Ryan Hagan
- National Institute for Bioprocessing Research and Training Dublin Ireland
- School of Chemical and Bioprocess EngineeringUniversity College Dublin Dublin Ireland
| | - Paul Kelly
- National Institute for Cellular BiotechnologyDublin City University Glasnevin Dublin Ireland
| | - Alan Costello
- National Institute for Cellular BiotechnologyDublin City University Glasnevin Dublin Ireland
| | - Justine Meiller
- National Institute for Cellular BiotechnologyDublin City University Glasnevin Dublin Ireland
| | - Patrick Floris
- National Institute for Bioprocessing Research and Training Dublin Ireland
| | - Lin Zhang
- Bioprocess R&DPfizer Inc. Andover Massachusetts
| | - Martin Clynes
- National Institute for Cellular BiotechnologyDublin City University Glasnevin Dublin Ireland
| | - Jonathan Bones
- National Institute for Bioprocessing Research and Training Dublin Ireland
- School of Chemical and Bioprocess EngineeringUniversity College Dublin Dublin Ireland
| | - Niall Barron
- National Institute for Bioprocessing Research and Training Dublin Ireland
- School of Chemical and Bioprocess EngineeringUniversity College Dublin Dublin Ireland
| | - Colin Clarke
- National Institute for Bioprocessing Research and Training Dublin Ireland
- School of Chemical and Bioprocess EngineeringUniversity College Dublin Dublin Ireland
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Abstract
The cell cycle is tightly regulated by cyclins and their catalytic moieties, the cyclin-dependent kinases (CDKs). Cyclin D1, in association with CDK4/6, acts as a mitogenic sensor and integrates extracellular mitogenic signals and cell cycle progression. When deregulated (overexpressed, accumulated, inappropriately located), cyclin D1 becomes an oncogene and is recognized as a driver of solid tumors and hemopathies. Recent studies on the oncogenic roles of cyclin D1 reported non-canonical functions dependent on the partners of cyclin D1 and its location within tumor cells or tissues. Support for these new functions was provided by various mouse models of oncogenesis. Finally, proteomic and transcriptomic data identified complex cyclin D1 networks. This review focuses on these aspects of cyclin D1 pathophysiology, which may be crucial for targeted therapy.Abbreviations: aa, amino acid; AR, androgen receptor; ATM, ataxia telangectasia mutant; ATR, ATM and Rad3-related; CDK, cyclin-dependent kinase; ChREBP, carbohydrate response element binding protein; CIP, CDK-interacting protein; CHK1/2, checkpoint kinase 1/2; CKI, CDK inhibitor; DDR, DNA damage response; DMP1, cyclin D-binding myb-like protein; DSB, double-strand DNA break; DNA-PK, DNA-dependent protein kinase; ER, estrogen receptor; FASN, fatty acid synthase; GSK3β, glycogen synthase-3β; HAT, histone acetyltransferase; HDAC, histone deacetylase; HK2, hexokinase 2; HNF4α, and hepatocyte nuclear factor 4α; HR, homologous recombination; IR, ionizing radiation; KIP, kinase inhibitory protein; MCL, mantle cell lymphoma; NHEJ, non-homologous end-joining; PCAF, p300/CREB binding-associated protein; PGC1α, PPARγ co-activator 1α; PEST, proline-glutamic acid-serine-threonine, PK, pyruvate kinase; PPAR, peroxisome proliferator-activated receptor; RB1, retinoblastoma protein; ROS, reactive oxygen species; SRC, steroid receptor coactivator; STAT, signal transducer and activator of transcription; TGFβ, transforming growth factor β; UPS, ubiquitin-proteasome system; USP22, ubiquitin-specific peptidase 22; XPO1 (or CRM1) exportin 1.
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Affiliation(s)
- Guergana Tchakarska
- Department of Human Genetics, McGill University Health Centre, McGill University, Montreal, Montreal, Quebec, Canada
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Qiu H, Cheng C, Wang Y, Kang M, Tang W, Chen S, Gu H, Liu C, Chen Y. Investigation of cyclin D1 rs9344 G>A polymorphism in colorectal cancer: a meta-analysis involving 13,642 subjects. Onco Targets Ther 2016; 9:6641-6650. [PMID: 27822068 PMCID: PMC5089821 DOI: 10.2147/ott.s116258] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The relationship between cyclin D1 (CCND1) rs9344 G>A polymorphism and colorectal cancer (CRC) risk is still ambiguous. To obtain a precise estimation of the relationship, we performed an extensive meta-analysis based on the eligible studies. Crude odds ratios with their 95% confidence intervals were harnessed to determine the strength of correlation between CCND1 rs9344 G>A polymorphism and CRC risk under the allele, the homozygote, the dominant, and the recessive genetic models, respectively (28 studies with 5,784 CRC cases and 7,858 controls). Our results indicated evidence of the association between CCND1 rs9344 G>A polymorphism and the increased risk of CRC in four genetic models: A vs G, AA vs GG, AA+GA vs GG, and AA vs GA+GG. In a stratified analysis by cancer type of CRC, there was an increased risk of sporadic CRC found in three genetic models: A vs G, AA vs GG, and AA+GA vs GG. In a stratified analysis by ethnicity, there was an increased CRC risk found among Asians in allele comparison genetic models, as well as Caucasians in two genetic models: AA+GA vs GG and A vs T. In summary, this meta-analysis demonstrates that CCND1 rs9344 G>A polymorphism may be a risk factor for CRC.
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Affiliation(s)
- Hao Qiu
- Department of Immunology, School of Medicine, Jiangsu University
| | - Chengguo Cheng
- Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang
| | - Yafeng Wang
- Department of Cardiology, The People's Hospital of Xishuangbanna Dai Autonomous Prefecture, Jinghong
| | - Mingqiang Kang
- Department of Thoracic Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou
| | - Weifeng Tang
- Department of Thoracic Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou; Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang
| | - Shuchen Chen
- Department of Thoracic Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou
| | - Haiyong Gu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai
| | - Chao Liu
- Department of Cardiothoracic Surgery, Affiliated People's Hospital of Jiangsu University, Zhenjiang
| | - Yu Chen
- Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Cancer Hospital; Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, People's Republic of China
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Weinhold N, Johnson DC, Chubb D, Chen B, Försti A, Hosking FJ, Broderick P, Ma YP, Dobbins SE, Hose D, Walker BA, Davies FE, Kaiser MF, Li NL, Gregory WA, Jackson GH, Witzens-Harig M, Neben K, Hoffmann P, Nöthen MM, Mühleisen TW, Eisele L, Ross FM, Jauch A, Goldschmidt H, Houlston RS, Morgan GJ, Hemminki K. The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma. Nat Genet 2013; 45:522-525. [PMID: 23502783 PMCID: PMC5056630 DOI: 10.1038/ng.2583] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 02/21/2013] [Indexed: 12/15/2022]
Abstract
A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 × 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.
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Affiliation(s)
- Niels Weinhold
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - David C Johnson
- Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Surrey, UK
| | - Daniel Chubb
- Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK
| | - Bowang Chen
- German Cancer Research Center, Heidelberg, Germany
| | - Asta Försti
- German Cancer Research Center, Heidelberg, Germany
- Center for Primary Health Care Research, Lund University, Malmo, Sweden
| | - Fay J Hosking
- Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK
| | - Peter Broderick
- Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK
| | - Yussanne P Ma
- Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK
| | - Sara E Dobbins
- Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK
| | - Dirk Hose
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
- National Centre for Tumour Diseases, Heidelberg, Germany
| | - Brian A Walker
- Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Surrey, UK
| | - Faith E Davies
- Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Surrey, UK
| | - Martin F Kaiser
- Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Surrey, UK
| | - Ni L Li
- Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Surrey, UK
| | | | | | | | - Kai Neben
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - Per Hoffmann
- Institute of Human Genetics, University of Bonn, Germany
| | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | | | - Lewin Eisele
- Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg–Essen, Essen, Germany
| | - Fiona M Ross
- Cytogenetics Group, Wessex Regional Cytogenetic Laboratory, Salisbury, UK
| | - Anna Jauch
- Institute of Human Genetics, University of Heidelberg, Germany
| | - Hartmut Goldschmidt
- Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
- National Centre for Tumour Diseases, Heidelberg, Germany
| | - Richard S Houlston
- Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, UK
| | - Gareth J Morgan
- Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Surrey, UK
| | - Kari Hemminki
- German Cancer Research Center, Heidelberg, Germany
- Center for Primary Health Care Research, Lund University, Malmo, Sweden
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Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M, Falaleeva M, Stamm S. Function of alternative splicing. Gene 2013; 514:1-30. [PMID: 22909801 PMCID: PMC5632952 DOI: 10.1016/j.gene.2012.07.083] [Citation(s) in RCA: 552] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Revised: 07/21/2012] [Accepted: 07/30/2012] [Indexed: 12/15/2022]
Abstract
Almost all polymerase II transcripts undergo alternative pre-mRNA splicing. Here, we review the functions of alternative splicing events that have been experimentally determined. The overall function of alternative splicing is to increase the diversity of mRNAs expressed from the genome. Alternative splicing changes proteins encoded by mRNAs, which has profound functional effects. Experimental analysis of these protein isoforms showed that alternative splicing regulates binding between proteins, between proteins and nucleic acids as well as between proteins and membranes. Alternative splicing regulates the localization of proteins, their enzymatic properties and their interaction with ligands. In most cases, changes caused by individual splicing isoforms are small. However, cells typically coordinate numerous changes in 'splicing programs', which can have strong effects on cell proliferation, cell survival and properties of the nervous system. Due to its widespread usage and molecular versatility, alternative splicing emerges as a central element in gene regulation that interferes with almost every biological function analyzed.
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Affiliation(s)
- Olga Kelemen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Paolo Convertini
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Zhaiyi Zhang
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Yuan Wen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Manli Shen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Marina Falaleeva
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Stefan Stamm
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
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Yang J, Zhang G, Chen J. CCND1 G870A polymorphism is associated with increased risk of colorectal cancer, especially for sporadic colorectal cancer and in Caucasians: a meta-analysis. Clin Res Hepatol Gastroenterol 2012; 36:169-77. [PMID: 22322158 DOI: 10.1016/j.clinre.2011.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Revised: 11/10/2011] [Accepted: 11/25/2011] [Indexed: 02/04/2023]
Abstract
AIMS To detect the association between G870A polymorphism of cyclin D1 (CCND1) gene and colorectal cancer. METHODS We performed a systematic literature and abstract search using PubMed, EMBase digital database. Keywords included CCND1, cyclin D1, polymorphism, SNP, colon cancer, rectal cancer and colorectal cancer. "And", "OR" and "NOT" were used as conjunction to narrow and widen the search. Data were extracted by two investigators independently, and meta-analysis was carried out by using Review Manager 4.2.8. The following pairwised combinations of genotypes for the CCND1 G870A polymorphism were evaluated: AA vs. GG, AG vs. GG, AA+AG vs. GG. Subsequently, sub-group analyses for cancer type, ethnicity, and the family history were performed. Sensitivity analysis was conducted by excluding the articles deviated from Hardy-Weinberg equilibrium. RESULTS Using GG genotype as a reference, A carriers were associated with a significantly increased cancer risk (OR=1.15, 95%CI=1.06-1.25, P=0.001, P(heterogeneity)=0.130), especially with rectal cancer (OR=1.24, 95%CI=1.02-1.51, P=0.030, P(heterogeneity)=0.570) and sporadic colorectal cancer (OR=1.26, 95%CI=1.08-1.46, P=0.003, P(heterogeneity)=0.730). The effect of A carriers on cancer also existed in Caucasians (OR=1.19, 95%CI=1.06-1.32, P=0.002, P(heterogeneity)=0.100). CONCLUSIONS CCND1 G870A polymorphism is associated with the increased risk of colorectal cancer, especially for sporadic colorectal cancer and in Caucasians.
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Affiliation(s)
- Jing Yang
- Department of gastroenterology, the Third Affiliated Hospital of Suzhou University, Changzhou, China.
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A defect of the INK4-Cdk4 checkpoint and Myc collaborate in blastoid mantle cell lymphoma-like lymphoma formation in mice. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:1688-701. [PMID: 22326754 DOI: 10.1016/j.ajpath.2012.01.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 12/02/2011] [Accepted: 01/03/2012] [Indexed: 12/30/2022]
Abstract
Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a monoclonal proliferation of lymphocytes with the co-expression of CD5 and CD43, but not of CD23. Typical MCL is associated with overexpression of cyclin D1, and blastoid MCL variants are associated with Myc (alias c-myc) translocations. In this study, we developed a murine model of MCL-like lymphoma by crossing Cdk4(R24C) mice with Myc-3'RR transgenic mice. The Cdk4(R24C) mouse is a knockin strain that expresses a Cdk4 protein that is resistant to inhibition by p16(INK4a) as well as other INK4 family members. Ablation of INK4 control on Cdk4 does not affect lymphomagenesis, B-cell maturation, and functions in Cdk4(R24C) mice. Additionally, B cells were normal in numbers, cell cycle activity, mitogen responsiveness, and Ig synthesis in response to activation. By contrast, breeding Cdk4(R24C) mice with Myc-3'RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma (CD19(+)IgM(+)IgD(+) cells) leads to the development of clonal blastoid MCL-like lymphoma (CD19(+)IgM(+)CD5(+)CD43(+)CD23(-) cells) in Myc/Cdk4(R24C) mice. Western blot analysis revealed high amounts of Cdk4/cyclin D1 complexes as the main hallmark of these lymphomas. These results indicate that although silent in nonmalignant B cells, a defect in the INK4-Cdk4 checkpoint can participate in lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation that might be reminiscent of the development of human blastoid MCL.
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10
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Hao M, Chen X, Zhang T, Shen T, Xie Q, Xing X, Gu H, Lu F. Impaired nuclear export of tumor-derived c-terminal truncated cyclin D1 mutant in ESCC cancer. Oncol Lett 2011; 2:1203-1211. [PMID: 22848289 DOI: 10.3892/ol.2011.404] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 08/17/2011] [Indexed: 11/06/2022] Open
Abstract
Cyclin D1 is a significant regulator of the G1- to S-phase transition and is often aberrant in human tumors of various origins. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms by which they contribute to neoplasia remaind to be elucidated. We previously identified a cyclin D1 mutation (Δ266-295) in esophageal cancer with deleted codons from 266 to 295 of wild-type cyclin D1, the critical COOH-terminal regulatory sequences necessary for cyclin D1 nuclear export. In the present study, this cancer-derived cyclin D1-Δ266-295 was shown to be a constitutively nuclear cyclin D1 protein with a significantly increased oncogenic potential. Moreover, the cancer-derived cyclin D1-Δ266-295 mutant was found to retain its ability to bind to and activate CDK4, which in turn phosphorylates and inactivates the pRb protein and promotes cell cycle progression. In comparison to wild-type cyclin D1a, D1-Δ266-295 exhibited enforced nuclear accumulation. In addition, the transient transfection and ectopic expression of this nuclear localized D1-Δ266-295 up-regulated endogenous Notch1 expression, indicating that the mutant retained its ability as a transcriptional regulator. Furthermore, data from the flow cytometry assay showed that D1-Δ266-295 fractionally increased >4N cell accumulation, and further analysis suggested the retriggering of DNA replication relevant to its inhibition of Cdt1 proteolysis. Therefore, the inappropriate nuclear localization of this cyclin D1 mutant may interfere with DNA replication in cultured cells, thereby contributing to genomic instability.
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Affiliation(s)
- Meili Hao
- Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081
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11
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Marsaud V, Tchakarska G, Andrieux G, Liu JM, Dembele D, Jost B, Wdzieczak-Bakala J, Renoir JM, Sola B. Cyclin K and cyclin D1b are oncogenic in myeloma cells. Mol Cancer 2010; 9:103. [PMID: 20459741 PMCID: PMC2881116 DOI: 10.1186/1476-4598-9-103] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Accepted: 05/10/2010] [Indexed: 11/10/2022] Open
Abstract
Background Aberrant expression of cyclin D1 is a common feature in multiple myeloma (MM) and always associated with mantle cell lymphoma (MCL). CCND1 gene is alternatively spliced to produce two cyclin D1 mRNA isoforms which are translated in two proteins: cyclin D1a and cyclin D1b. Both isoforms are present in MM cell lines and primary cells but their relative role in the tumorigenic process is still elusive. Results To test the tumorigenic potential of cyclin D1b in vivo, we generated cell clones derived from the non-CCND1 expressing MM LP-1 cell line, synthesizing either cyclin D1b or cyclin K, a structural homolog and viral oncogenic form of cyclin D1a. Immunocompromised mice injected s.c. with LP-1K or LP-1D1b cells develop tumors at the site of injection. Genome-wide analysis of LP-1-derived cells indicated that several cellular processes were altered by cyclin D1b and/or cyclin K expression such as cell metabolism, signal transduction, regulation of transcription and translation. Importantly, cyclin K and cyclin D1b have no major action on cell cycle or apoptosis regulatory genes. Moreover, they impact differently cell functions. Cyclin K-expressing cells have lost their migration properties and display enhanced clonogenic capacities. Cyclin D1b promotes tumorigenesis through the stimulation of angiogenesis. Conclusions Our study indicates that cyclin D1b participates into MM pathogenesis via previously unrevealed actions.
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Affiliation(s)
- Véronique Marsaud
- Biologie Moléculaire et Cellulaire de la Signalisation, EA 3919, IFR 146, Université de Caen, Caen, France
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Paronetto MP, Cappellari M, Busà R, Pedrotti S, Vitali R, Comstock C, Hyslop T, Knudsen KE, Sette C. Alternative splicing of the cyclin D1 proto-oncogene is regulated by the RNA-binding protein Sam68. Cancer Res 2009; 70:229-39. [PMID: 20028857 DOI: 10.1158/0008-5472.can-09-2788] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Human cyclin D1 is expressed as two isoforms derived by alternate RNA splicing, termed D1a and D1b, which differ for the inclusion of intron 4 in the D1b mRNA. Both isoforms are frequently upregulated in human cancers, but cyclin D1b displays relatively higher oncogenic potential. The splicing factors that regulate alternative splicing of cyclin D1b remain unknown despite the likelihood that they contribute to cyclin D1 oncogenicity. In this study, we report that Sam68, an RNA-binding protein frequently overexpressed in prostate cancer cells, enhances splicing of cyclin D1b and supports its expression in prostate cancer cells. Chromatin immunoprecipitation and RNA coimmunoprecipitation experiments showed that Sam68 is recruited to the human CCND1 gene encoding cyclin D1 and that it binds to cyclin D1 mRNA. Transient overexpression and RNAi knockdown experiments indicated that Sam68 acts to enhance endogenous expression of cyclin D1b. Minigene reporter assays showed that Sam68 directly affected alternative splicing of CCND1 message, with a preference for the A870 allele that is known to favor cyclin D1b splicing. Sam68 interacted with the proximal region of intron 4, and its binding correlated inversely with recruitment of the spliceosomal component U1-70K. Sam68-mediated splicing was modulated by signal transduction pathways that elicit phosphorylation of Sam68 and regulate its affinity for CCND1 intron 4. Notably, Sam68 expression positively correlates with levels of cyclin D1b, but not D1a, in human prostate carcinomas. Our results identify Sam68 as the first splicing factor to affect CCND1 alternative splicing in prostate cancer cells, and suggest that increased levels of Sam68 may stimulate cyclin D1b expression in human prostate cancers.
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Affiliation(s)
- Maria Paola Paronetto
- Department of Public Health and Cell Biology, University of Rome Tor Vergata, Rome, Italy
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Comstock CE, Augello MA, Benito RP, Karch J, Tran TH, Utama FE, Tindall EA, Wang Y, Burd CJ, Groh EM, Hoang HN, Giles GG, Severi G, Hayes VM, Henderson BE, Marchand LL, Kolonel LN, Haiman CA, Baffa R, Gomella LG, Knudsen ES, Rui H, Henshall SM, Sutherland RL, Knudsen KE. Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer. Clin Cancer Res 2009; 15:5338-49. [PMID: 19706803 PMCID: PMC2849314 DOI: 10.1158/1078-0432.ccr-08-2865] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. EXPERIMENTAL DESIGN First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies. RESULTS Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. CONCLUSIONS These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism.
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Affiliation(s)
- Clay E.S. Comstock
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Michael A. Augello
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Ruth Pe Benito
- Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
| | - Jason Karch
- Department of Cell and Cancer Biology, University of Cincinnati, Cincinnati, Ohio
| | - Thai H. Tran
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Fransiscus E. Utama
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Elizabeth A. Tindall
- Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
- Cancer Genetics, Children's Cancer Institute Australia for Medical Research, University of New South Wales, Randwick, NSW, Australia
| | - Ying Wang
- Department of Cell and Cancer Biology, University of Cincinnati, Cincinnati, Ohio
| | - Craig J. Burd
- National Institutes of Environmental Health Science, Research Triangle Park, North Carolina
| | - Eric M. Groh
- Department of Cell and Cancer Biology, University of Cincinnati, Cincinnati, Ohio
| | - Hoa N. Hoang
- The Cancer Council of Victoria, Carlton, Melbourne, Victoria, Australia
| | - Graham G. Giles
- The Cancer Council of Victoria, Carlton, Melbourne, Victoria, Australia
| | - Gianluca Severi
- The Cancer Council of Victoria, Carlton, Melbourne, Victoria, Australia
| | - Vanessa M. Hayes
- Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
- Cancer Genetics, Children's Cancer Institute Australia for Medical Research, University of New South Wales, Randwick, NSW, Australia
| | - Brian E. Henderson
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Loic Le Marchand
- Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii
| | - Laurence N. Kolonel
- Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii
| | - Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Raffaele Baffa
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department Urology, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Leonard G. Gomella
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department Urology, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Erik S. Knudsen
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Hallgeir Rui
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia Pennsylvania
| | - Susan M. Henshall
- Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
| | - Robert L. Sutherland
- Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia
| | - Karen E. Knudsen
- Kimmel Cancer Center, Thomas Jefferson University, Philadelphia Pennsylvania
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia Pennsylvania
- Department Urology, Thomas Jefferson University, Philadelphia Pennsylvania
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Kim CJ, Nishi K, Isono T, Okuyama Y, Tambe Y, Okada Y, Inoue H. Cyclin D1b variant promotes cell invasiveness independent of binding to CDK4 in human bladder cancer cells. Mol Carcinog 2009; 48:953-64. [DOI: 10.1002/mc.20547] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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15
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Expression of cyclin D1 splice variants is differentially associated with outcome in non-small cell lung cancer patients. Hum Pathol 2008; 39:1792-801. [DOI: 10.1016/j.humpath.2008.05.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Revised: 05/10/2008] [Accepted: 05/14/2008] [Indexed: 11/21/2022]
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16
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Gupta VK, Feber A, Xi L, Pennathur A, Wu M, Luketich JD, Godfrey TE. Association between CCND1 G/A870 polymorphism, allele-specific amplification, cyclin D1 expression, and survival in esophageal and lung carcinoma. Clin Cancer Res 2008; 14:7804-12. [PMID: 19047108 PMCID: PMC2723959 DOI: 10.1158/1078-0432.ccr-08-0744] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE Cyclin D1 is found on 11q13, which is a region frequently amplified in several tumor types. The CCND1 locus gives rise to at least two protein isoforms of D1 (D1a and D1b). A common G/A polymorphism (G/A870) is thought to influence the expression levels of D1a and D1b. D1b has been suggested to be increased in the presence of the A allele and more oncogenic than D1a. Furthermore, the A allele has been reported to correlate with increased risk of carcinoma in several tumor types, suggesting that this polymorphism and D1b are important in tumor progression. However, contradictory data about the polymorphism, D1 variant expression, and correlation with survival have been reported. We explored the relationship between gene amplification, G/A870 genotype, D1a and D1b expression, and overall survival in esophageal adenocarcinoma and non-small cell lung cancer. EXPERIMENTAL DESIGN DNA and RNA were isolated from 54 esophageal adenocarcinoma samples and 89 non-small cell lung cancer samples and were analyzed for gene amplification, genotype at the polymorphism, gene expression, and association with overall survival. RESULTS The D1 variant expression did not correlate with amplification, genotype, or overall survival in either tumor type. The total D1 expression correlated with decreased patient survival. Several other genes on 11q13 also seem to be overexpressed and correlated with decreased survival. CONCLUSIONS We report that the G/A870 polymorphism does not correlate with patient survival, or with D1a or D1b expression. However, the total D1 expression and the expression of several other genes on 11q13 seem to be associated with esophageal adenocarcinoma patient survival.
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Affiliation(s)
- Vanita K. Gupta
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - Andrew Feber
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - Liqiang Xi
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - Arjun Pennathur
- Heart, Lung and Esophageal Surgery Institute, and Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Maoxin Wu
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
| | - James D Luketich
- Heart, Lung and Esophageal Surgery Institute, and Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Tony E. Godfrey
- Department of Pathology, Mount Sinai School of Medicine, New York, NY
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Li Z, Wang C, Jiao X, Katiyar S, Casimiro MC, Prendergast GC, Powell MJ, Pestell RG. Alternate cyclin D1 mRNA splicing modulates p27KIP1 binding and cell migration. J Biol Chem 2008; 283:7007-15. [PMID: 18180298 DOI: 10.1074/jbc.m706992200] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cyclin D1 is an important cell cycle regulator, but in cancer its overexpression also increases cellular migration mediated by p27 KIP1 stabilization and RhoA inhibition. Recently, a common polymorphism at the exon 4-intron 4 boundary of the human cyclin D1 gene within a splice donor region was associated with an altered risk of developing cancer. Altered RNA splicing caused by this polymorphism gives rise to a variant cyclin D1 isoform termed cyclin D1b, which has the same N terminus as the canonical cyclin D1a isoform but a distinct C terminus. In this study we show that these different isoforms have unique properties with regard to the cellular migration function of cyclin D1. Although they displayed little difference in transcriptional co-repression assays on idealized reporter genes, microarray cDNA expression analysis revealed differential regulation of genes, including those that influence cellular migration. Additionally, whereas cyclin D1a stabilized p27 KIP1 and inhibited RhoA-induced ROCK kinase activity, promoting cellular migration, cyclin D1b failed to stabilize p27 KIP1 or inhibit ROCK kinase activity and had no effect on migration. Our findings argue that alternate splicing is an important determinant of the function of cyclin D1 in cellular migration.
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Affiliation(s)
- Zhiping Li
- Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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