cyclin dependent kinase 6

Summary

Summary: Cyclin-dependent kinase 6 associates with CYCLIN D and phosphorylates RETINOBLASTOMA PROTEIN during G1 PHASE of the CELL CYCLE. It helps regulate the transition to S PHASE and its kinase activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P18.

Top Publications

  1. Fiaschi Taesch N, Bigatel T, Sicari B, Takane K, Salim F, Velazquez Garcia S, et al. Survey of the human pancreatic beta-cell G1/S proteome reveals a potential therapeutic role for cdk-6 and cyclin D1 in enhancing human beta-cell replication and function in vivo. Diabetes. 2009;58:882-93 pubmed publisher
    ..Using this model, human beta-cell replication can be induced and studied in vivo. ..
  2. Kohrt D, Crary J, Gocheva V, Hinds P, Grossel M. Distinct subcellular distribution of cyclin dependent kinase 6. Cell Cycle. 2009;8:2837-43 pubmed
    ..The results of this study may help to better understand the emerging roles of cdk6 in cell cycle control, differentiation and cancer. ..
  3. Michaud K, Solomon D, Oermann E, Kim J, Zhong W, Prados M, et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 2010;70:3228-38 pubmed publisher
    ..In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. ..
  4. Heiferman M, Salabat M, Ujiki M, Strouch M, Cheon E, Silverman R, et al. Sansalvamide induces pancreatic cancer growth arrest through changes in the cell cycle. Anticancer Res. 2010;30:73-8 pubmed
    ..Cumulatively the results show that Sansalvamide A attenuates pancreatic cancer cell growth and represents a potential anticancer therapy. ..
  5. Zhao J, Lin J, Lwin T, Yang H, Guo J, Kong W, et al. microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood. 2010;115:2630-9 pubmed publisher
    ..Thus, our findings provide not only miRNA expression signature but also a novel prognostic marker and pathogenetic factor for this malignancy. ..
  6. Cerqueira A, Santamaria D, Martinez Pastor B, Cuadrado M, Fernandez Capetillo O, Barbacid M. Overall Cdk activity modulates the DNA damage response in mammalian cells. J Cell Biol. 2009;187:773-80 pubmed publisher
    ..Our results reveal that genome maintenance programs of postreplicative cells, including DDR, are regulated by the overall level of Cdk activity and not by specific Cdks. ..
  7. Cole A, Myant K, Reed K, Ridgway R, Athineos D, van den Brink G, et al. Cyclin D2-cyclin-dependent kinase 4/6 is required for efficient proliferation and tumorigenesis following Apc loss. Cancer Res. 2010;70:8149-58 pubmed publisher
  8. Nguyen H, Lavrenov S, Sundar S, Nguyen D, Tseng M, Marconett C, et al. 1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells. Chem Biol Interact. 2010;186:255-66 pubmed publisher
  9. Wiedemeyer W, Dunn I, Quayle S, Zhang J, Chheda M, Dunn G, et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci U S A. 2010;107:11501-6 pubmed publisher
    ..More generally, these observations demonstrate that the integration of genomic, functional and pharmacologic data can be exploited to inform the development of targeted therapy directed against specific cancer pathways. ..

More Information

Publications53

  1. Wu J, Qian J, Li C, Kwok L, Cheng F, Liu P, et al. miR-129 regulates cell proliferation by downregulating Cdk6 expression. Cell Cycle. 2010;9:1809-18 pubmed
    ..Together, our data indicate that miR-129 plays an important role in regulating cell proliferation by downregulation of Cdk6. ..
  2. Tsuji K, Yasui K, Gen Y, Endo M, Dohi O, Zen K, et al. PEG10 is a probable target for the amplification at 7q21 detected in hepatocellular carcinoma. Cancer Genet Cytogenet. 2010;198:118-25 pubmed publisher
    ..These results suggest that PEG10 is a probable target, acting as a driving force for amplification of the 7q21 region, and may therefore be involved in the development or progression of HCCs. ..
  3. Duan H, Jiang Y, Zhang H, Wu Y. MiR-320 and miR-494 affect cell cycles of primary murine bronchial epithelial cells exposed to benzo[a]pyrene. Toxicol In Vitro. 2010;24:928-35 pubmed publisher
  4. Gumina M, Xu C, Chiles T. Cyclin D3 is dispensable for human diffuse large B-cell lymphoma survival and growth: evidence for redundancy with cyclin E. Cell Cycle. 2010;9:820-8 pubmed
    ..Taken together, these results uncover a built-in redundancy with cyclins D3 and E for G(1)-S progression. Moreover these findings highlight the rationale for simultaneous disruption of cdk4/6 as a potential therapeutic cancer strategy. ..
  5. Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, et al. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res. 2009;69:7569-76 pubmed publisher
    ..They show that miR-34a suppresses brain tumor growth by targeting c-Met and Notch. The results also suggest that miR-34a could serve as a potential therapeutic agent for brain tumors. ..
  6. Finn R, Dering J, Conklin D, Kalous O, Cohen D, Desai A, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:R77 pubmed publisher
    ..These studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991 ..
  7. Cho Y, Borland M, Brain C, Chen C, Cheng H, Chopra R, et al. 4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6. J Med Chem. 2010;53:7938-57 pubmed publisher
    ..Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays. ..
  8. Tokcaer Keskin Z, Dikmen Z, Ayaloglu Butun F, Gultekin S, Gryaznov S, Akcali K. The effect of telomerase template antagonist GRN163L on bone-marrow-derived rat mesenchymal stem cells is reversible and associated with altered expression of cyclin d1, cdk4 and cdk6. Stem Cell Rev. 2010;6:224-33 pubmed publisher
    ..Our study provides additional support for treating cancers by administrating GRN163L without depleting the body's stem cell pools. ..
  9. Kalamvoki M, Roizman B. Interwoven roles of cyclin D3 and cdk4 recruited by ICP0 and ICP4 in the expression of herpes simplex virus genes. J Virol. 2010;84:9709-17 pubmed publisher
  10. Yang X, Feng M, Jiang X, Wu Z, Li Z, Aau M, et al. miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Genes Dev. 2009;23:2388-93 pubmed publisher
  11. Hsia T, Yang J, Chen G, Chiu T, Lu H, Yang M, et al. The roles of endoplasmic reticulum stress and Ca2+ on rhein-induced apoptosis in A-549 human lung cancer cells. Anticancer Res. 2009;29:309-18 pubmed
    ..Our data demonstrate that rhein induces apoptosis in A-549 cells via a Ca2+ -dependent mitochondrial pathway. ..
  12. Yang Z, Cao Y, Zhu X, Huang Y, Ding Y, Liu X. Znhit1 causes cell cycle arrest and down-regulates CDK6 expression. Biochem Biophys Res Commun. 2009;386:146-52 pubmed publisher
    ..These findings identified Znhit1 as a CDK6 regulator that plays an important role in cell proliferation. ..
  13. Sun Y, Cai T, Zhou X, Xu Q. Saikosaponin a inhibits the proliferation and activation of T cells through cell cycle arrest and induction of apoptosis. Int Immunopharmacol. 2009;9:978-83 pubmed publisher
    ..This may herald a novel approach for further studies of saikosaponin a as a candidate for the treatment of inflammatory and autoimmune diseases. ..
  14. Inaba H, Kuboniwa M, Bainbridge B, Yilmaz O, Katz J, Shiverick K, et al. Porphyromonas gingivalis invades human trophoblasts and inhibits proliferation by inducing G1 arrest and apoptosis. Cell Microbiol. 2009;11:1517-32 pubmed publisher
    ..gingivalis can invade placental trophoblasts and induce G1 arrest and apoptosis through pathways involving ERK1/2 and its downstream effectors, properties that provide a mechanistic basis for pathogenicity in complications of pregnancy. ..
  15. Gan L, Liu P, Lu H, Chen S, Yang J, McCarthy J, et al. Cyclin D1 promotes anchorage-independent cell survival by inhibiting FOXO-mediated anoikis. Cell Death Differ. 2009;16:1408-17 pubmed publisher
    ..These data suggest that cyclin D1 may have a critical function in tumorigenesis and cancer metastasis by inhibiting the anoikis-promoting function of FOXO proteins. ..
  16. Agirre X, Vilas Zornoza A, Jimenez Velasco A, Martin Subero J, Cordeu L, Garate L, et al. Epigenetic silencing of the tumor suppressor microRNA Hsa-miR-124a regulates CDK6 expression and confers a poor prognosis in acute lymphoblastic leukemia. Cancer Res. 2009;69:4443-53 pubmed publisher
    ..005) in the multivariate analysis. These results provide the grounds for new therapeutic strategies in ALL either targeting the epigenetic regulation of microRNAs and/or directly targeting the CDK6-Rb pathway. ..
  17. Graf F, Mosch B, Koehler L, Bergmann R, Wuest F, Pietzsch J. Cyclin-dependent kinase 4/6 (cdk4/6) inhibitors: perspectives in cancer therapy and imaging. Mini Rev Med Chem. 2010;10:527-39 pubmed
    ..The potential of Cdk4/6 inhibitors, particularly, pyrido[2,3-d]pyrimidine derivatives, as both anti-cancer drugs and 124I- and 18F-radiolabeled tracers for cancer imaging using positron emission tomography is discussed. ..
  18. Baranda Avila N, Mendoza Rodriguez C, Morimoto S, Langley E, Cerbón M. Molecular mechanism of cell proliferation in rodent uterus during the estrous cycle. J Steroid Biochem Mol Biol. 2009;113:259-68 pubmed publisher
  19. Dean J, Thangavel C, McClendon A, Reed C, Knudsen E. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 2010;29:4018-32 pubmed publisher
    ..Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic. ..
  20. Zabel du Bois A, Wagner Ecker M, Milker Zabel S, Schwager C, Wirkner U, Debus J, et al. Gene expression signatures in the peripheral blood after radiosurgery of human cerebral arteriovenous malformations. Strahlenther Onkol. 2010;186:91-98 pubmed publisher
    ..The identified genes indicate a potential new methodology to monitor RS, which may result in an individualized therapy and optimized follow-up. ..
  21. Isinger Ekstrand A, Johansson J, Ohlsson M, Francis P, Staaf J, Jonsson M, et al. Genetic profiles of gastroesophageal cancer: combined analysis using expression array and tiling array--comparative genomic hybridization. Cancer Genet Cytogenet. 2010;200:120-6 pubmed publisher
    ..These data suggest that molecular diagnostics and targeted therapies can be applied to adenocarcinomas of the distal esophagus and gastroesophageal junction alike. ..
  22. Tay S, Yeo C, Chai C, Chua P, Tan H, Ang A, et al. Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells. J Biol Chem. 2010;285:29231-8 pubmed publisher
    ..Taken together, our results support a negative role for parkin in tumorigenesis and provide a potential mechanism by which parkin exerts its suppressing effects on breast cancer cell proliferation. ..
  23. Fiaschi Taesch N, Salim F, Kleinberger J, Troxell R, Cozar Castellano I, Selk K, et al. Induction of human beta-cell proliferation and engraftment using a single G1/S regulatory molecule, cdk6. Diabetes. 2010;59:1926-36 pubmed publisher
    ..Unexpectedly, cyclin D3 and cdk6 overexpression drives human beta-cell replication most effectively. Most importantly, a single molecule, cdk6, supports robust human beta-cell proliferation and function in vivo. ..
  24. Rodríguez Ubreva F, Cariaga Martinez A, Cortes M, Romero De Pablos M, Ropero S, Lopez Ruiz P, et al. Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/S progression in prostate cancer cells through the regulation of components of the cell-cycle machinery. Oncogene. 2010;29:345-55 pubmed publisher
    ..This study shows that SHP-1 depletion promotes cell-cycle arrest by modulating the activity of cell-cycle regulators and suggests that SHP-1 may be required for the proper functioning of events governing cell-cycle progression. ..
  25. Lee K, Lotterman C, Karikari C, Omura N, Feldmann G, Habbe N, et al. Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology. 2009;9:293-301 pubmed publisher
  26. Chen D, Law M, Theis J, Gamez J, Caron L, Vrana J, et al. Clinicopathologic features of CDK6 translocation-associated B-cell lymphoproliferative disorders. Am J Surg Pathol. 2009;33:720-9 pubmed publisher
    ..These distinct clinicopathologic and cytogenetic features distinguish the CDK6 translocation-associated BLPDs (CDK6-BLPDs) from other mature B-cell lymphomas. ..
  27. Hu M, Deshpande A, Enos M, Mao D, Hinds E, Hu G, et al. A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res. 2009;69:810-8 pubmed publisher
    ..These results show a critical requirement for CDK6 in Notch/Akt-dependent T-cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies. ..
  28. Sarek G, Järviluoma A, Moore H, Tojkander S, Vartia S, Biberfeld P, et al. Nucleophosmin phosphorylation by v-cyclin-CDK6 controls KSHV latency. PLoS Pathog. 2010;6:e1000818 pubmed publisher
    ..This work demonstrates that NPM is a critical regulator of KSHV latency via functional interactions with v-cyclin and LANA. ..
  29. Yoshioka H, Noguchi K, Katayama K, Mitsuhashi J, Yamagoe S, Fujimuro M, et al. Functional availability of gamma-herpesvirus K-cyclin is regulated by cellular CDK6 and p16INK4a. Biochem Biophys Res Commun. 2010;394:1000-5 pubmed publisher
    ..Our data suggest that the balance between CDK6 and p16INK4a regulates the availability of functional K-cyclin in human cells. ..
  30. Bockstaele L, Bisteau X, Paternot S, Roger P. Differential regulation of cyclin-dependent kinase 4 (CDK4) and CDK6, evidence that CDK4 might not be activated by CDK7, and design of a CDK6 activating mutation. Mol Cell Biol. 2009;29:4188-200 pubmed publisher
    ..Moreover, they provide a new model of a potentially oncogenic activating mutation of a CDK. ..
  31. Samant G, Wali V, Sylvester P. Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif. 2010;43:77-83 pubmed publisher
  32. Li F, Lu L, Lu J. Identification and location of label retaining cells in mouse liver. J Gastroenterol. 2010;45:113-21 pubmed publisher
    ..Moreover, HSPCs still retained labels and located definitively in the periportal region after a prolonged chase. The LRC method together with our novel KAL method reported here may be used to identify and locate possible HSPCs. ..
  33. Shi L, Zhang J, Pan T, Zhou J, Gong W, Liu N, et al. MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation. Brain Res. 2010;1312:120-6 pubmed publisher
    ..These findings underscore the potential of miR-125b to regulate the proliferation of U251 glioma stem cells through the cell cycle regulated proteins CDK6 and CDC25A. ..
  34. Orozco G, Eyre S, Hinks A, Ke X, Wilson A, Bax D, et al. Association of CD40 with rheumatoid arthritis confirmed in a large UK case-control study. Ann Rheum Dis. 2010;69:813-6 pubmed publisher
    ..8 x 10(-8), OR 0.87 (95% CI 0.83 to 0.92). In this large UK cohort, strong association of the CD40 gene with susceptibility to RA was found, and weaker evidence for association with RA in the CCL21 locus. ..
  35. Weng J, Omar H, Kulp S, Chen C. Pharmacological exploitation of indole-3-carbinol to develop potent antitumor agents. Mini Rev Med Chem. 2010;10:398-404 pubmed
    ..Thus, this minireview focuses on the chemical biology of the lead optimization of these indole derivatives. ..
  36. McKenzie H, Fung C, Becker T, Irvine M, Mann G, Kefford R, et al. Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A. Hum Mutat. 2010;31:692-701 pubmed publisher
    ..The ability to determine variant functional activity accurately would identify disease-associated mutations and facilitate effective genetic counselling of individuals at high risk of melanoma. ..
  37. Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P, Khan G, et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell. 2010;18:63-73 pubmed publisher
    ..These observations suggest that robust and selective pharmacological inhibition of Cdk4 may provide therapeutic benefit for NSCLC patients carrying K-RAS oncogenes. ..
  38. Choe K, Ujhelly O, Wontakal S, Skoultchi A. PU.1 directly regulates cdk6 gene expression, linking the cell proliferation and differentiation programs in erythroid cells. J Biol Chem. 2010;285:3044-52 pubmed publisher
  39. Chebel A, Kagialis Girard S, Catallo R, Chien W, Mialou V, Domenech C, et al. Indirubin derivatives inhibit malignant lymphoid cell proliferation. Leuk Lymphoma. 2009;50:2049-60 pubmed publisher
    ..Taken together, these results showed that IO and, moreover, its derivative 6BIO may be potent antiproliferative agents in malignant lymphoid cells. ..
  40. Klein M, Mayo K, Kratzke R. p16(INK4a) Peptide mimetics identified via virtual screening. Bioorg Med Chem Lett. 2010;20:403-5 pubmed publisher
    ..Four compounds were subsequently shown to inhibit Cdk4 and/or Cdk6 with IC(50) in the muM range. These compounds form lead compounds upon which further cell cycle inhibitors can be developed. ..
  41. Lizé M, Pilarski S, Dobbelstein M. E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis. Cell Death Differ. 2010;17:452-8 pubmed publisher
    ..While responding to different transactivators, miRNAs 449 and 34 each repress E2F1, but promote p53 activity, allowing efficient cross-talk between two major DNA damage-responsive gene regulators. ..
  42. Rivadeneira D, Mayhew C, Thangavel C, Sotillo E, Reed C, Grana X, et al. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology. 2010;138:1920-30 pubmed publisher
    ..These data show that CDK4/6 inhibition is a potent mediator of cytostasis and that RB loss can be readily compensated for in the context of both hepatoma cell lines and liver tissue. ..
  43. Zhong Z, Yeow W, Zou C, Wassell R, Wang C, Pestell R, et al. Cyclin D1/cyclin-dependent kinase 4 interacts with filamin A and affects the migration and invasion potential of breast cancer cells. Cancer Res. 2010;70:2105-14 pubmed publisher
  44. Arakawa Takeuchi S, Kobayashi K, Park J, Uranbileg B, Yamamoto H, Jinno S, et al. Mammalian target of rapamycin complex 1 signaling opposes the effects of anchorage loss, leading to activation of Cdk4 and Cdc6 stabilization. FEBS Lett. 2010;584:2779-85 pubmed publisher