Genomes and Genes
cyclin dependent kinase 4
Summary: Cyclin-dependent kinase 4 is a key regulator of G1 PHASE of the CELL CYCLE. It partners with CYCLIN D to phosphorylate RETINOBLASTOMA PROTEIN. CDK4 activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P16.
- 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. ..
- Blanchet E, Annicotte J, Fajas L. Cell cycle regulators in the control of metabolism. Cell Cycle. 2009;8:4029-31 pubmed..There is enough evidence to indicate that the CDK4-pRB-E2F1 regulatory pathway is involved in general glucose homeostasis, and metabolism. In this article we discuss which are the metabolic implications of these findings. ..
- 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 ..
- Zhang D, Al Hendy M, Richard Davis G, Montgomery Rice V, Rajaratnam V, Al Hendy A. Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertil Steril. 2010;94:1887-93 pubmed publisher..Epigallocatechin gallate inhibits the proliferation of HuLM cells and induces apoptosis. These results suggest that EGCG may be a potential anti-uterine fibroid agent acting through multiple signal transduction pathways. ..
- Horvai A, Devries S, Roy R, O Donnell R, Waldman F. Similarity in genetic alterations between paired well-differentiated and dedifferentiated components of dedifferentiated liposarcoma. Mod Pathol. 2009;22:1477-88 pubmed publisher..The relationship between genetic changes and presentation or grade may reflect differences in factors that control genomic instability or the background genotype of the tumor...
- Kim S, Myoung H, Choung P, Kim M, Lee S, Lee J. Metastatic leiomyosarcoma in the oral cavity: case report with protein expression profiles. J Craniomaxillofac Surg. 2009;37:454-60 pubmed publisher..A total of seven cases of metastatic LMS to the oral cavity that had been published in the English literature were reviewed, and the reason for the poor prognosis in the metastatic LMS is suggested in this case report. ..
- Aubry C, Wilson A, Emmerson D, Murphy E, Chan Y, Dickens M, et al. Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1. Bioorg Med Chem. 2009;17:6073-84 pubmed publisher..We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC(50) for the best compounds 10m and 13a being 39 and 37microm, respectively. ..
- Johnson S, Torrice C, Bell J, Monahan K, Jiang Q, Wang Y, et al. Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest. 2010;120:2528-36 pubmed publisher..These results demonstrate an effective method to mitigate the hematopoietic toxicity of IR in mammals, which may be potentially useful after radiological disaster or as an adjuvant to anticancer therapy. ..
- Raychaudhuri S, Fontanes V, Barat B, Dasgupta A. Activation of ribosomal RNA transcription by hepatitis C virus involves upstream binding factor phosphorylation via induction of cyclin D1. Cancer Res. 2009;69:2057-64 pubmed publisher..These results could, at least in part, explain a mechanism by which HCV contributes to transformation of liver cells. ..
- Muth D, Ghazaryan S, Eckerle I, Beckett E, Pöhler C, Batzler J, et al. Transcriptional repression of SKP2 is impaired in MYCN-amplified neuroblastoma. Cancer Res. 2010;70:3791-802 pubmed publisher..Together, this implies that deregulated MYCN protein levels in MYCN-amplified neuroblastoma cells activate SKP2 through CDK4 induction, abrogating repressive pRB-E2F1 complexes bound to the SKP2 promoter. ..
- Benson D, Yu J, Becknell B, Wei M, Freud A, Ferketich A, et al. Stem cell factor and interleukin-2/15 combine to enhance MAPK-mediated proliferation of human natural killer cells. Blood. 2009;113:2706-14 pubmed publisher..Collectively the data reveal a novel mechanism by which SCF enhances cellular proliferation in combination with IL-2/15 in primary human NK cells. ..
- Zhou H, Shen T, Luo Y, Liu L, Chen W, Xu B, et al. The antitumor activity of the fungicide ciclopirox. Int J Cancer. 2010;127:2467-77 pubmed publisher..The results indicate that CPX is a potential antitumor agent. ..
- de Vreeze R, de Jong D, Nederlof P, Ariaens A, Tielen I, Frenken L, et al. Added Value of Molecular Biological Analysis in Diagnosis and Clinical Management of Liposarcoma: A 30-Year Single-Institution Experience. Ann Surg Oncol. 2010;17:686-93 pubmed publisher..Treatment decisions and prognosis assessment for liposarcoma is based on a classification that depends on morphological and genetic features. Revisions by experienced referral pathologists are often advocated...
- 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. ..
- Kim H, Huang W, Jiang X, Pennicooke B, Park P, Johnson M. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc Natl Acad Sci U S A. 2010;107:2183-8 pubmed publisher..Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways. ..
- Roig A, Eskiocak U, Hight S, Kim S, Delgado O, Souza R, et al. Immortalized epithelial cells derived from human colon biopsies express stem cell markers and differentiate in vitro. Gastroenterology. 2010;138:1012-21.e1-5 pubmed publisher..We established immortalized HCECs that are capable of self-renewal and multilineage differentiation. These cells should serve as valuable reagents for studying colon stem cell biology, differentiation, and pathogenesis. ..
- Chan H, Yip H, Mak N, Leung K. Modulatory effects and action mechanisms of tryptanthrin on murine myeloid leukemia cells. Cell Mol Immunol. 2009;6:335-42 pubmed publisher..Collectively, our findings suggest that tryptanthrin might exert its anti-tumor effect on the murine myelomonocytic leukemia WEHI-3B JCS cells by causing cell cycle arrest and by triggering cell differentiation. ..
- Mazar J, Sinha S, Dinger M, Mattick J, Perera R. Protein-coding and non-coding gene expression analysis in differentiating human keratinocytes using a three-dimensional epidermal equivalent. Mol Genet Genomics. 2010;284:1-9 pubmed publisher..The current studies lay the foundation for relevant model systems to address such fundamentally important biological aspects of epidermal structure and function in normal and diseased human skin. ..
- Lee J, Jo J, Hardikar A, Periwal V, Rane S. Cdk4 regulates recruitment of quiescent beta-cells and ductal epithelial progenitors to reconstitute beta-cell mass. PLoS ONE. 2010;5:e8653 pubmed publisher..Comparing the contribution of cell proliferation and islet-like clusters to the total increase in insulin-positive cells suggests a hitherto uncharacterized large non-proliferative contribution. ..
- Ma J, Zhao M, Yu X. [Effects of histone deacetylase inhibitor MS-275 on expression of survivin and NF-kappaB in the human myeloma cell line U266 cells]. Zhonghua Zhong Liu Za Zhi. 2009;31:250-3 pubmed..MS-275-induced apoptosis of U266 cells is mediated by downregulation of expression of survivin and inactivation of NF-kappaB survival signalling pathways. ..
- Shimura T, Kakuda S, Ochiai Y, Nakagawa H, Kuwahara Y, Takai Y, et al. Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3beta-mediated cyclin D1 overexpression. Oncogene. 2010;29:4826-37 pubmed publisher..Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors. ..
- Liu Q, Loo W, Sze S, Tong Y. Curcumin inhibits cell proliferation of MDA-MB-231 and BT-483 breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription. Phytomedicine. 2009;16:916-22 pubmed publisher..Our finding extrapolates the antitumor activity of curcumin in mediating the breast cancer cell proliferative rate and invasion by down-regulating the NFkappaB inducing genes. ..
- 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. ..
- Anderson A, Child E, Prasad A, Elphick L, Mann D. Cyclin D1 and cyclin D3 show divergent responses to distinct mitogenic stimulation. J Cell Physiol. 2010;225:638-45 pubmed publisher..These findings uncover additional levels of complexity in the regulation of the cell cycle at the level of the D-type cyclins and thus may have important therapeutic implications in cancers where specific D-cyclins are overexpressed. ..
- O Carroll S, Mitchell M, Faenza I, Cocco L, Gilmour R. Nuclear PLCbeta1 is required for 3T3-L1 adipocyte differentiation and regulates expression of the cyclin D3-cdk4 complex. Cell Signal. 2009;21:926-35 pubmed..These results indicate nuclear PLCbeta1 as a key regulator of adipocyte differentiation. ..
- Cui W, De Jesus K, Zhao H, Takasawa S, Shi B, Srikant C, et al. Overexpression of Reg3alpha increases cell growth and the levels of cyclin D1 and CDK4 in insulinoma cells. Growth Factors. 2009;27:195-202 pubmed publisher..Our results suggest that Reg3alpha stimulates beta-cell replication, by activating Akt kinase and increasing the levels of cyclin D1/CDK4. ..
- Andrade C, Takahama Junior A, Nishimoto I, Kowalski L, Lopes M. Rhabdomyosarcoma of the head and neck: a clinicopathological and immunohistochemical analysis of 29 cases. Braz Dent J. 2010;21:68-73 pubmed..5%), C-erbB2 in 19 cases (70.4%), FAS in 9 cases (31%), PCNA in 28 cases (96.5%) and Ki67 in 16 cases (55.2%). The overall survival was 28.7% in 5 and 10 years, and p53 expression may be related with poor prognosis. ..
- Jeong J, Jeong H. 2-Methoxy-4-vinylphenol can induce cell cycle arrest by blocking the hyper-phosphorylation of retinoblastoma protein in benzo[a]pyrene-treated NIH3T3 cells. Biochem Biophys Res Commun. 2010;400:752-7 pubmed publisher..Our results suggest that 2M4VP induce growth arrest of BaP-treated NIH 3T3 cells by blocking the hyper-phosphorylation of Rb via regulating the expression of cell cycle-related proteins. ..
- 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. ..
- Kim J, Diehl J. Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol. 2009;220:292-6 pubmed publisher..This review provides a brief overview of current data documenting various mechanisms underlying aberrant cyclin D1 regulation in human cancers and their impact on neoplastic transformation. ..
- Zhu H, Xiao X, Zheng J, Zheng S, Dong K, Yu Y. Growth-promoting effect of bisphenol A on neuroblastoma in vitro and in vivo. J Pediatr Surg. 2009;44:672-80 pubmed publisher..Bisphenol A can promote the growth of neuroblastoma to a level similar to that of E(2). Estrogen receptor-dependent pathway and angiogenesis may contribute to the underlying mechanisms. ..
- Aggarwal P, Vaites L, Kim J, Mellert H, Gurung B, Nakagawa H, et al. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell. 2010;18:329-40 pubmed publisher..Importantly, human cancers harboring mutations in Fbx4, the cyclin D1 E3 ligase, exhibit nuclear cyclin D1 accumulation and increased PRMT5 activity. ..
- 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. ..
- Sakairi T, Abe Y, Jat P, Kopp J. Cell-cell contact regulates gene expression in CDK4-transformed mouse podocytes. Am J Physiol Renal Physiol. 2010;299:F802-9 pubmed publisher..Our findings suggest that CDK4 podocytes are useful tools to study podocyte biology. Furthermore, the role of cell-cell contact in podocyte gene expression may have relevance for podocyte function in vivo. ..
- Steed E, Balda M, Matter K. Dynamics and functions of tight junctions. Trends Cell Biol. 2010;20:142-9 pubmed publisher..Combining such dynamic properties with existing tight junction models will help us to advance our understanding of the molecular mechanisms that underlie the functional properties of tight junctions. ..
- Liu N, Fang H, Li Y, Xu W. Recent research in selective cyclin-dependent kinase 4 inhibitors for anti-cancer treatment. Curr Med Chem. 2009;16:4869-88 pubmed..This review will give the recent progress in the studies of structure, functions of CDK4 and highly selective and potent CDK4 inhibitors. ..
- Lange C, Huttner W, Calegari F. Cdk4/cyclinD1 overexpression in neural stem cells shortens G1, delays neurogenesis, and promotes the generation and expansion of basal progenitors. Cell Stem Cell. 2009;5:320-31 pubmed publisher..Thus, G1 lengthening is necessary and sufficient to switch neural progenitors to neurogenesis, and overexpression of cdk4/cyclinD1 can be used to increase progenitor expansion and, perhaps, cortical surface area. ..
- Tsai C, Chiu S, Liu C, Sheu T, Hsieh C, Keng P, et al. Regulated expression of cofilin and the consequent regulation of p27(kip1) are essential for G(1) phase progression. Cell Cycle. 2009;8:2365-74 pubmed..These data suggest that cofilin expression and its regulation of p27(kip1) expression is important for the control of G(1) phase progression. ..
- Sun J, Li Z, Hu Z, Zeng Z, Yang D, Jiang W. Apogossypolone inhibits cell growth by inducing cell cycle arrest in U937 cells. Oncol Rep. 2009;22:193-8 pubmed..These findings suggest that ApoG2 may be a potential chemotherapeutic agent for the treatment of cancer. ..
- Pei X, Bai F, Smith M, Usary J, Fan C, Pai S, et al. CDK inhibitor p18(INK4c) is a downstream target of GATA3 and restrains mammary luminal progenitor cell proliferation and tumorigenesis. Cancer Cell. 2009;15:389-401 pubmed publisher..Hence, p18(INK4C) is a downstream target of GATA3, constrains luminal progenitor cell expansion, and suppresses luminal tumorigenesis in the mammary gland. ..
- 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. ..
- Li Z, Shao S, Xie S, Jiao F, Ma Y, Shi S. Silencing of CT120 by antisense oligonucleotides could inhibit the lung cancer cells growth. Ir J Med Sci. 2010;179:217-23 pubmed publisher..CT120 may play an important role in tumor progression, and the down-regulation of CT120 expression could be a new drug target candidate in the treatment of lung cancer. ..
- Li J, Xu M, Yang Z, Li A, Dong J. Simultaneous inhibition of MEK and CDK4 leads to potent apoptosis in human melanoma cells. Cancer Invest. 2010;28:350-6 pubmed publisher..Our results indicate that simultaneously targeting ERK and RB pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations. ..
- Blancquaert S, Wang L, Paternot S, Coulonval K, Dumont J, Harris T, et al. cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4. Mol Endocrinol. 2010;24:1453-68 pubmed publisher..We propose that mTORC1 activation by TSH, at least in part through PKA-dependent phosphorylation of PRAS40, crucially contributes to mediate cAMP-dependent mitogenesis by regulating CDK4 T172-phosphorylation. ..
- Lee H, Yuk J, Shin D, Yang C, Kim K, Choi D, et al. Apurinic/apyrimidinic endonuclease 1 is a key modulator of keratinocyte inflammatory responses. J Immunol. 2009;183:6839-48 pubmed publisher..Taken together, these findings establish a role for APE1 as a master regulator of TLR2-dependent inflammatory responses in human keratinocytes. ..
- Meenakshisundaram R, Gragnoli C. CDK4 IVS4-nt40G-->A and T2D-associated obesity in Italians. J Cell Physiol. 2009;221:273-5 pubmed publisher..Hence, CDK4 IVS4-nt40A allele is protective and G allele confers risk for obesity in T2D patients. This study should prompt further work aiming at establishing CDK4 role in contributing to human obesity and T2D-associated obesity. ..
- Kannengiesser C, Brookes S, del Arroyo A, Pham D, Bombled J, Barrois M, et al. Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients. Hum Mutat. 2009;30:564-74 pubmed publisher..Discriminating between mutant and neutral variants of p16(INK4A) not only adds to our understanding of the functionally critical residues in the protein but provides information that can be used for melanoma risk prediction. ..
- Smalley K, Contractor R, Nguyen T, Xiao M, Edwards R, Muthusamy V, et al. Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression. Cancer Res. 2008;68:5743-52 pubmed publisher..This group of melanomas may be a subpopulation for which imatinib or other KIT inhibitors may constitute optimal therapy. ..