fbpx
Wikipedia

Cyclin-dependent kinase 6

February 26, 2023

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene.[5][6] It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins.[7] The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4.[8] CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.[9]

CDK6
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDK6, MCPH12, PLSTIRE, cyclin-dependent kinase 6, cyclin dependent kinase 6
External IDsOMIM: 603368 MGI: 1277162 HomoloGene: 963 GeneCards: CDK6
Orthologs
SpeciesHumanMouse
Entrez

1021

12571

Ensembl

ENSG00000105810

ENSMUSG00000040274

UniProt

Q00534

Q64261

RefSeq (mRNA)

NM_001145306
NM_001259

NM_009873

RefSeq (protein)

NP_001138778
NP_001250

NP_034003

Location (UCSC)Chr 7: 92.6 – 92.84 MbChr 5: 3.39 – 3.58 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

This kinase is a catalytic subunit of the protein kinase complex, important for the G1 phase progression and G1/S transition of the cell cycle and the complex is composed also by an activating sub-unit; the cyclin D.[10] The activity of this kinase first appears in mid-G1 phase, which is controlled by the regulatory subunits including D-type cyclins and members of INK4 family of CDK inhibitors.[7] This kinase, as well as CDK4, has been shown to phosphorylate, and thus regulate the activity of, tumor suppressor Retinoblastoma protein making CDK6 an important protein in cancer development.[10]

Structure

The CDK6 gene is conserved in eukaryotes, including the budding yeast and the nematode Caenorhabditis elegans.[11] The CDK6 gene is located on chromosome 7 in humans. The gene spans 231,706 base pairs and encodes a 326 amino acid protein with a kinase function.[6] The gene is overexpressed in cancers like lymphoma, leukemia, medulloblastoma and melanoma associated with chromosomal rearrangements.[6] The CDK6 protein contains a catalytic core composed of a serine/threonine domain.[12] This protein also contains an ATP-binding pocket, inhibitory and activating phosphorylation sites, a PSTAIRE-like cyclin-binding domain and an activating T-loop motif.[10] After binding the Cyclin in the PSTAIRE helix, the protein changes its conformational structure to expose the phosphorylation motif.[10] The protein can be found in the cytoplasm and the nucleus, however most of the active complexes are found in the nucleus of proliferating cells.[10]

Function

Cell cycle

In 1994, Matthew Meyerson and Ed Harlow investigated the product of a close analogous gene of CDK4.[7] This gene, identified as PLSTIRE was translated into a protein that interacted with the cyclins CD1, CD2 and CD3 (same as CDK4), but that was different from CDK4; the protein was then renamed CDK6 for simplicity.[7] In mammalian cells, cell cycle is activated by CDK6 in the early G1 phase[13] through interactions with cyclins D1, D2 and D3.[7] There are many changes in gene expression that are regulated through this enzyme.[14] After the complex is formed, the C-CDK6 enzymatic complex phosphorylates the protein pRb.[15] After its phosphorylation, pRb releases its binding partner E2F, a transcriptional activator, which in turn activates DNA replication.[16] The CDK6 complex ensures a point of switch to commit to division responding to external signals, like mitogens and growth factors.[17]

CDK6 is involved in a positive feedback loop that activates transcription factors through a reaction cascade.[18] Importantly, these C-CDK complexes act as a kinase, phosphorylating and inactivating the protein of Rb and p-Rb related “pocket proteins” p107 and p130.[19] While doing this, the CDK6 in conjunction with CDK4, act as a switch signal that first appears in G1,[7] directing the cell towards S phase of the cell cycle.[14]

CDK6 is important for the control of G1 to S phase transition.[7] However, in recent years, new evidence proved that the presence of CDK6 is not essential for proliferation in every cell type,[20] the cell cycle has a complex circuitry of regulation and the role of CDK6 might be more important in certain cell types than in others, where CDK4 or CDK2 can act as protein kinases compensating its role.[20][21]

Cellular development

In mutant Knockout mice of CDK6, the hematopoietic function is impaired, regardless of otherwise organism normal development.[20] This might hint additional roles of CDK6 in the development of blood components.[20] There are additional functions of CDK6 not associated with its kinase activity.[22] For example, CDK6 is involved in the differentiation of T cells, acting as an inhibitor of differentiation.[22] Even though CDK6 and CDK4 share 71% amino acid identity, this role in differentiation is unique to CDK6.[22] CDK6 has also been found to be important in the development of other cell lines, for example, CDK6 has a role in the alteration of the morphology of astrocytes[23] and in the development of other stem cells.[10][16]

DNA protection

CDK6 differs from CDK4 in other important roles.[24] For example, CDK6 plays a role in the accumulation of the apoptosis proteins p53 and p130, this accumulation keeps cells from entering cell division if there is DNA damage, activating pro- apoptotic pathways.[24]

Metabolic homeostasis

Studies in the metabolic control of cells have revealed yet another role of CDK6.[25] This new role is associated with the balance of the oxidative and non-oxidative branches of the pentose pathway in cells.[25] This pathway is a known route altered in cancer cells, when there is an aberrant overexpression of CDK6 and CDK4.[25] The overexpression of these proteins provides the cancer cells with a new hallmark capability of cancer; the deregulation of the cell metabolism.[25]

Centrosome stability

In 2013, researchers discovered yet another role of CDK6.[26] There is evidence that CDK6 associates with the centrosome and controls organized division and cell cycle phases in neuron production.[26] When the CDK6 gene is mutated in these developing lines, the centrosomes are not properly divided, this could lead to division problems such as aneuploidy, which in turns leads to health issues like primary microcephaly.[26]

Mechanisms of regulation

CDK6 is positively regulated primarily by its union to the D cyclins D1, D2 and D3. If this subunit of the complex is not available, CDK6 is not active or available to phosphorylate the Rb substrate.[9] An additional positive activator needed by CDK6 is the phosphorylation in a conserved threonine residue located in 177 position, this phosphorylation is done by the cdk-activating kinases, CAK.[27] Additionally, CDK6 can be phosphorylated and activated by the Kaposi's sarcoma-associated herpes virus, stimulating the CDK6 over activation and uncontrolled cell proliferation.[28]

CDK6 is negatively regulated by binding to certain inhibitors that can be classified in two groups;[29] CKIs or CIP/KIP family members like the protein p21[16] and p27 act blocking and inhibiting the assembled C-CDKs binding complex enzymes[27] in their catalytic domain.[30]

Furthermore, inhibitors of the INK4 family members like p15, p16, p18 and p19 inhibit the monomer of CDK6, preventing the complex formation.[19][31]

Clinical relevance

CDK6 is a protein kinase activating cell proliferation, it is involved in an important point of restriction in the cell cycle.[18] For this reason, CDK6 and other regulators of the G1 phase of the cell cycle are known to be unbalanced in more than 80-90% of tumors.[9] In cervical cancer cells, CDK6 function has been shown to be altered indirectly by the p16 inhibitor.[31] CDK6 is also overexpressed in tumors that exhibit drug resistance, for example glioma malignancies exhibit resistance to chemotherapy using temozolomide (TMZ) when they have a mutation overexpressing CDK6.[32] Likewise, the overexpression of CDK6 is also associated with resistance to hormone therapy using the anti oestrogen Fluvestrant in breast cancer.[33]

Cancer

Loss of normal cell cycle control is the first step to developing different hallmarks of cancer; alterations of CDK6 can directly or indirectly affect the following hallmarks; disregulated cell cellular energetics, sustaining of proliferative signaling, evading growth suppressors and inducing angiogenesis,[9] for example, deregulation of CDK6 has been shown to be important in lymphoid malignancies by increasing angiogenesis, a hallmark of cancer.[19] These features are reached through upregulation of CDK6 due to chromosome alterations or epigenetic dysregulations.[9] Additionally, CDK6 might be altered through genomic instability, a mechanism of downregulation of tumor suppressor genes; this represents another evolving hallmark of cancer.[34]

Medulloblastoma

Medulloblastoma is the most common cause of brain cancer in children.[35] About a third of these cancers have upregulated CDK6, representing a marker for poor prognosis for this disease.[35] Since it is so common for these cells to have alterations in CDK6, researchers are seeking for ways to downregulate CDK6 expression acting specifically in those cell lines. The MicroRNA (miR) -124 has successfully controlled cancer progression in an in-vitro setting for medulloblastoma and glioblastoma cells.[35] Furthermore, researchers have found that it successfully reduces the growth of xenograft tumors in rat models.[35]

As a drug target

Further information: CDK inhibitor

The direct targeting of CDK6 and CDK4 should be used with caution in the treatment of cancer, because these enzymes are important for the cell cycle of normal cells as well.[35] Furthermore, small molecules targeting these proteins might increase drug resistance events.[35] However, these kinases have been shown to be useful as coadjuvants in breast cancer chemotherapy.[36] Another indirect mechanism for the control of CDK6 expression, is the use of a mutated D-cyclin that binds with high affinity to CDK6, but does not induce its kinase activity.[36] this mechanism was studied in the development of mammary tumorigenesis in rat cells, however, the clinical effects have not yet been shown in human patients.[36] A

Interactions

Cyclin-dependent kinase 6 interacts with:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000105810 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040274 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH (Aug 1992). "A family of human cdc2-related protein kinases". The EMBO Journal. 11 (8): 2909–17. doi:10.1002/j.1460-2075.1992.tb05360.x. PMC 556772. PMID 1639063.
  6. ^ a b c "Entrez Gene: CDK6 cyclin-dependent kinase 6".
  7. ^ a b c d e f g Meyerson, M; Harlow, E (1994). "Identification of G1 Kinase Activity for cdk6, a Novel Cyclin D Partner". Molecular and Cellular Biology. 14 (3): 2077–86. doi:10.1128/MCB.14.3.2077. PMC 358568. PMID 8114739.
  8. ^ Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, and Jon C. Aster | eBook on, accessed April 21, 2014, https://www.inkling.com/store/book/robbins-basic-pathology-kumar-abbas-aster-9th/?chapterId=d0de80fcb2d4401c91c3045fcf0f45e1.
  9. ^ a b c d e Diaz-Moralli S, Tarrado-Castellarnau M, Miranda A, Cascante M (May 2013). "Targeting cell cycle regulation in cancer therapy". Pharmacology & Therapeutics. 138 (2): 255–71. doi:10.1016/j.pharmthera.2013.01.011. PMID 23356980.
  10. ^ a b c d e f Lim S, Kaldis P (Aug 2013). "Cdks, cyclins and CKIs: roles beyond cell cycle regulation". Development. 140 (15): 3079–93. doi:10.1242/dev.091744. PMID 23861057.
  11. ^ Liu, Ji; Kipreos, Edward T. (2000). "Evolution of Cyclin-Dependent Kinases (CDKs) and CDK-Activating Kinases (CAKs): Differential Conservation of CAKs in Yeast and Metazoa". Molecular Biology and Evolution. 17 (7): 1061–74. doi:10.1093/oxfordjournals.molbev.a026387. PMID 10889219.
  12. ^ Reinhardt HC, Yaffe MB (Sep 2013). "Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response". Nature Reviews Molecular Cell Biology. 14 (9): 563–80. doi:10.1038/nrm3640. PMID 23969844. S2CID 149598.
  13. ^ Harvey Lodish et al., Molecular Cell Biology. 4th Edition., 2000, https://www.ncbi.nlm.nih.gov/books/NBK21497/.
  14. ^ a b Bertoli C, Skotheim JM, de Bruin RA (Aug 2013). "Control of cell cycle transcription during G1 and S phases". Nature Reviews Molecular Cell Biology. 14 (8): 518–28. doi:10.1038/nrm3629. PMC 4569015. PMID 23877564.
  15. ^ Ezhevsky SA, Ho A, Becker-Hapak M, Davis PK, Dowdy SF (Jul 2001). "Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo". Molecular and Cellular Biology. 21 (14): 4773–84. doi:10.1128/MCB.21.14.4773-4784.2001. PMC 87164. PMID 11416152.
  16. ^ a b c Grossel MJ, Hinds PW (Feb 2006). "Beyond the cell cycle: a new role for Cdk6 in differentiation". Journal of Cellular Biochemistry. 97 (3): 485–93. doi:10.1002/jcb.20712. PMID 16294322. S2CID 41684216.
  17. ^ Bartek, J; Lukas, J (2001). "Mammalian G1- and S-Phase Checkpoints in Response to DNA Damage". Current Opinion in Cell Biology. 13 (6): 738–47. doi:10.1016/s0955-0674(00)00280-5. PMID 11698191.
  18. ^ a b Aarts M, Linardopoulos S, Turner NC (Aug 2013). "Tumour selective targeting of cell cycle kinases for cancer treatment". Current Opinion in Pharmacology. 13 (4): 529–35. doi:10.1016/j.coph.2013.03.012. PMID 23597425.
  19. ^ a b c Kollmann K, Heller G, Schneckenleithner C, Warsch W, Scheicher R, Ott RG, Schäfer M, Fajmann S, Schlederer M, Schiefer AI, Reichart U, Mayerhofer M, Hoeller C, Zöchbauer-Müller S, Kerjaschki D, Bock C, Kenner L, Hoefler G, Freissmuth M, Green AR, Moriggl R, Busslinger M, Malumbres M, Sexl V (Aug 2013). "A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis". Cancer Cell. 24 (2): 167–81. doi:10.1016/j.ccr.2013.07.012. PMC 3743049. PMID 23948297.
  20. ^ a b c d Katarzyna Kozar and Piotr Sicinski, "Cell Cycle Progression without Cyclin D-CDK4 and Cyclin D-CDK6 Complexes," Cell Cycle 4, no. 3 (March 2005): 388–91
  21. ^ Malumbres M, Sotillo R, Santamaría D, Galán J, Cerezo A, Ortega S, Dubus P, Barbacid M (Aug 2004). "Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6". Cell. 118 (4): 493–504. doi:10.1016/j.cell.2004.08.002. PMID 15315761. S2CID 13371605.
  22. ^ a b c Martha J Grossel and Philip W Hinds, "From Cell Cycle to Differentiation: An Expanding Role for cdk6," Cell Cycle 5, no. 3 (February 2006): 266–70
  23. ^ Ericson, Karen K.; et al. (2003). "Expression of Cyclin-Dependent Kinase 6, but Not Cyclin-Dependent Kinase 4, Alters Morphology of Cultured Mouse Astrocytes11NSF under CAREER Grant #9984454 to Martha J. Grossel". Molecular Cancer Research. 1 (9): 654–64.
  24. ^ a b Nagasawa M, Gelfand EW, Lucas JJ (May 2001). "Accumulation of high levels of the p53 and p130 growth-suppressing proteins in cell lines stably over-expressing cyclin-dependent kinase 6 (cdk6)". Oncogene. 20 (23): 2889–99. doi:10.1038/sj.onc.1204396. PMID 11420701.
  25. ^ a b c d Zanuy M, Ramos-Montoya A, Villacañas O, Canela N, Miranda A, Aguilar E, Agell N, Bachs O, Rubio-Martinez J, Pujol MD, Lee WN, Marin S, Cascante M (Jun 2012). "Cyclin-dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle". Metabolomics. 8 (3): 454–64. doi:10.1007/s11306-011-0328-x. PMC 3361763. PMID 22661920.
  26. ^ a b c Hussain, Muhammad S; et al. (2013). "CDK6 Associates with the Centrosome during Mitosis and Is Mutated in a Large Pakistani Family with Primary Microcephaly". Human Molecular Genetics. 22 (25): 5199–5214. doi:10.1093/hmg/ddt374. PMID 23918663.
  27. ^ a b LaBaer, J; et al. (1997). "New Functional Activities for the p21 Family of CDK Inhibitors". Genes & Development. 11 (7): 847–62. doi:10.1101/gad.11.7.847. PMID 9106657.
  28. ^ Kaldis P (Mar 2005). "The N-terminal peptide of the Kaposi's sarcoma-associated herpesvirus (KSHV)-cyclin determines substrate specificity". The Journal of Biological Chemistry. 280 (12): 11165–74. doi:10.1074/jbc.M408887200. PMID 15664993.
  29. ^ Nurse, P (2000). "A Long Twentieth Century of the Cell Cycle and beyond". Cell. 100 (1): 71–78. doi:10.1016/s0092-8674(00)81684-0. PMID 10647932. S2CID 16366539.
  30. ^ Bockstaele L, Kooken H, Libert F, Paternot S, Dumont JE, de Launoit Y, Roger PP, Coulonval K (Jul 2006). "Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK "inhibitors"". Molecular and Cellular Biology. 26 (13): 5070–85. doi:10.1128/MCB.02006-05. PMC 1489149. PMID 16782892.
  31. ^ a b Khleif, S N; et al. (1996). "Inhibition of Cyclin D-CDK4/CDK6 Activity Is Associated with an E2F-Mediated Induction of Cyclin Kinase Inhibitor Activity". Proceedings of the National Academy of Sciences of the United States of America. 93 (9): 4350–54. Bibcode:1996PNAS...93.4350K. doi:10.1073/pnas.93.9.4350. PMC 39540. PMID 8633069.
  32. ^ Li B, He H, Tao BB, Zhao ZY, Hu GH, Luo C, Chen JX, Ding XH, Sheng P, Dong Y, Zhang L, Lu YC (Sep 2012). "Knockdown of CDK6 enhances glioma sensitivity to chemotherapy". Oncology Reports. 28 (3): 909–14. doi:10.3892/or.2012.1884. PMID 22736304.
  33. ^ Giessrigl B, Schmidt WM, Kalipciyan M, Jeitler M, Bilban M, Gollinger M, Krieger S, Jäger W, Mader RM, Krupitza G (Nov 2013). "Fulvestrant induces resistance by modulating GPER and CDK6 expression: implication of methyltransferases, deacetylases and the hSWI/SNF chromatin remodelling complex". British Journal of Cancer. 109 (10): 2751–62. doi:10.1038/bjc.2013.583. PMC 3833203. PMID 24169358.
  34. ^ Negrini S, Gorgoulis VG, Halazonetis TD (Mar 2010). "Genomic instability--an evolving hallmark of cancer". Nature Reviews Molecular Cell Biology. 11 (3): 220–28. doi:10.1038/nrm2858. PMID 20177397. S2CID 10217969.
  35. ^ a b c d e f Silber J, Hashizume R, Felix T, Hariono S, Yu M, Berger MS, Huse JT, VandenBerg SR, James CD, Hodgson JG, Gupta N (Jan 2013). "Expression of miR-124 inhibits growth of medulloblastoma cells". Neuro-Oncology. 15 (1): 83–90. doi:10.1093/neuonc/nos281. PMC 3534424. PMID 23172372.
  36. ^ a b c Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW (Jan 2006). "Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis". Cancer Cell. 9 (1): 13–22. doi:10.1016/j.ccr.2005.12.019. PMID 16413468.
  37. ^ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3: 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
  38. ^ Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y (Dec 1994). "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function". Genes & Development. 8 (24): 2939–52. doi:10.1101/gad.8.24.2939. PMID 8001816.
  39. ^ Jeffrey PD, Tong L, Pavletich NP (Dec 2000). "Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors". Genes & Development. 14 (24): 3115–25. doi:10.1101/gad.851100. PMC 317144. PMID 11124804.
  40. ^ a b Lin J, Jinno S, Okayama H (Apr 2001). "Cdk6-cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell's proliferation competence". Oncogene. 20 (16): 2000–9. doi:10.1038/sj.onc.1204375. PMID 11360184.
  41. ^ Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E (Nov 1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes & Development. 13 (22): 3027–33. doi:10.1101/gad.13.22.3027. PMC 317153. PMID 10580009.
  42. ^ Meyerson M, Harlow E (Mar 1994). "Identification of G1 kinase activity for cdk6, a novel cyclin D partner". Molecular and Cellular Biology. 14 (3): 2077–86. doi:10.1128/MCB.14.3.2077. PMC 358568. PMID 8114739.
  43. ^ Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP (Jan 1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A" (PDF). Current Biology. 6 (1): 84–91. doi:10.1016/s0960-9822(02)00425-6. PMID 8805225. S2CID 23024663.
  44. ^ Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP (Sep 1998). "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a". Nature. 395 (6699): 237–43. Bibcode:1998Natur.395..237R. doi:10.1038/26155. PMID 9751050. S2CID 204997058.
  45. ^ Kaldis P, Ojala PM, Tong L, Mäkelä TP, Solomon MJ (Dec 2001). "CAK-independent activation of CDK6 by a viral cyclin". Molecular Biology of the Cell. 12 (12): 3987–99. doi:10.1091/mbc.12.12.3987. PMC 60770. PMID 11739795.
  46. ^ a b Cheng A, Kaldis P, Solomon MJ (Nov 2000). "Dephosphorylation of human cyclin-dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms". The Journal of Biological Chemistry. 275 (44): 34744–9. doi:10.1074/jbc.M006210200. PMID 10934208.

Further reading

  • Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O (Sep 1995). "Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence" (PDF). Nature. 377 (6547 Suppl): 3–174. PMID 7566098.
  • Aprelikova O, Xiong Y, Liu ET (Aug 1995). "Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase". The Journal of Biological Chemistry. 270 (31): 18195–7. doi:10.1074/jbc.270.31.18195. PMID 7629134.
  • Lucas JJ, Szepesi A, Modiano JF, Domenico J, Gelfand EW (Jun 1995). "Regulation of synthesis and activity of the PLSTIRE protein (cyclin-dependent kinase 6 (cdk6)), a major cyclin D-associated cdk4 homologue in normal human T lymphocytes". Journal of Immunology. 154 (12): 6275–84. PMID 7759865.
  • Bullrich F, MacLachlan TK, Sang N, Druck T, Veronese ML, Allen SL, Chiorazzi N, Koff A, Heubner K, Croce CM (Mar 1995). "Chromosomal mapping of members of the cdc2 family of protein kinases, cdk3, cdk6, PISSLRE, and PITALRE, and a cdk inhibitor, p27Kip1, to regions involved in human cancer". Cancer Research. 55 (6): 1199–205. PMID 7882308.
  • Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y (Dec 1994). "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function". Genes & Development. 8 (24): 2939–52. doi:10.1101/gad.8.24.2939. PMID 8001816.
  • Meyerson M, Harlow E (Mar 1994). "Identification of G1 kinase activity for cdk6, a novel cyclin D partner". Molecular and Cellular Biology. 14 (3): 2077–86. doi:10.1128/MCB.14.3.2077. PMC 358568. PMID 8114739.
  • Fåhraeus R, Paramio JM, Ball KL, Laín S, Lane DP (Jan 1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A" (PDF). Current Biology. 6 (1): 84–91. doi:10.1016/S0960-9822(02)00425-6. PMID 8805225. S2CID 23024663.
  • Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
  • Lamphere L, Fiore F, Xu X, Brizuela L, Keezer S, Sardet C, Draetta GF, Gyuris J (Apr 1997). "Interaction between Cdc37 and Cdk4 in human cells". Oncogene. 14 (16): 1999–2004. doi:10.1038/sj.onc.1201036. PMID 9150368.
  • Nagasawa M, Melamed I, Kupfer A, Gelfand EW, Lucas JJ (Jun 1997). "Rapid nuclear translocation and increased activity of cyclin-dependent kinase 6 after T cell activation". Journal of Immunology. 158 (11): 5146–54. PMID 9164930.
  • Ezhevsky SA, Nagahara H, Vocero-Akbani AM, Gius DR, Wei MC, Dowdy SF (Sep 1997). "Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb". Proceedings of the National Academy of Sciences of the United States of America. 94 (20): 10699–704. Bibcode:1997PNAS...9410699E. doi:10.1073/pnas.94.20.10699. PMC 23451. PMID 9380698.
  • Fåhraeus R, Laín S, Ball KL, Lane DP (Feb 1998). "Characterization of the cyclin-dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule". Oncogene. 16 (5): 587–96. doi:10.1038/sj.onc.1201580. PMID 9482104.
  • Gonzales AJ, Goldsworthy TL, Fox TR (Jun 1998). "Chemical transformation of mouse liver cells results in altered cyclin D-CDK protein complexes". Carcinogenesis. 19 (6): 1093–102. doi:10.1093/carcin/19.6.1093. PMID 9667749.
  • Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP (Sep 1998). "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a". Nature. 395 (6699): 237–43. Bibcode:1998Natur.395..237R. doi:10.1038/26155. PMID 9751050. S2CID 204997058.
  • Brotherton DH, Dhanaraj V, Wick S, Brizuela L, Domaille PJ, Volyanik E, Xu X, Parisini E, Smith BO, Archer SJ, Serrano M, Brenner SL, Blundell TL, Laue ED (Sep 1998). "Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d". Nature. 395 (6699): 244–50. Bibcode:1998Natur.395..244B. doi:10.1038/26164. PMID 9751051. S2CID 13337394.
  • Jiang W, Wells NJ, Hunter T (May 1999). "Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6". Proceedings of the National Academy of Sciences of the United States of America. 96 (11): 6193–8. Bibcode:1999PNAS...96.6193J. doi:10.1073/pnas.96.11.6193. PMC 26858. PMID 10339564.
  • Yarbrough WG, Buckmire RA, Bessho M, Liu ET (Sep 1999). "Biologic and biochemical analyses of p16(INK4a) mutations from primary tumors". Journal of the National Cancer Institute. 91 (18): 1569–74. doi:10.1093/jnci/91.18.1569. PMID 10491434.
  • Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC (Sep 1999). "Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1". Cell. 98 (6): 859–69. doi:10.1016/S0092-8674(00)81519-6. PMID 10499802. S2CID 14025897.
  • Grossel MJ, Baker GL, Hinds PW (Oct 1999). "cdk6 can shorten G(1) phase dependent upon the N-terminal INK4 interaction domain". The Journal of Biological Chemistry. 274 (42): 29960–7. doi:10.1074/jbc.274.42.29960. PMID 10514479.

External links

February 26, 2023
cyclin, dependent, kinase, cell, division, protein, kinase, cdk6, enzyme, encoded, cdk6, gene, regulated, cyclins, more, specifically, cyclin, proteins, cyclin, dependent, kinase, inhibitor, proteins, protein, encoded, this, gene, member, cyclin, dependent, ki. Cell division protein kinase 6 CDK6 is an enzyme encoded by the CDK6 gene 5 6 It is regulated by cyclins more specifically by Cyclin D proteins and Cyclin dependent kinase inhibitor proteins 7 The protein encoded by this gene is a member of the cyclin dependent kinase CDK family which includes CDK4 8 CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28 and Schizosaccharomyces pombe cdc2 and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point 9 CDK6Available structuresPDBOrtholog search PDBe RCSBList of PDB id codes1BI7 1BI8 1BLX 1G3N 1JOW 1XO2 2EUF 2F2C 3NUP 3NUX 4AUA 4EZ5 4TTHIdentifiersAliasesCDK6 MCPH12 PLSTIRE cyclin dependent kinase 6 cyclin dependent kinase 6External IDsOMIM 603368 MGI 1277162 HomoloGene 963 GeneCards CDK6Gene location Human Chr Chromosome 7 human 1 Band7q21 2Start92 604 921 bp 1 End92 836 573 bp 1 Gene location Mouse Chr Chromosome 5 mouse 2 Band5 A1 5 2 04 cMStart3 391 485 bp 2 End3 581 008 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed incancellous bonepyloruscaput epididymiscardianippleparietal pleuracavity of mouthinferior ganglion of vagus nervebone marrowrenal medullaTop expressed inconjunctival fornixvas deferensPaneth cellinternal carotid arteryatriummedial ganglionic eminenceexternal carotid arterythymusleft lung lobemaxillary prominenceMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functiontransferase activity protein kinase activity nucleotide binding cyclin dependent protein serine threonine kinase activity kinase activity protein serine threonine kinase activity protein binding ATP binding cyclin binding FBXO family protein bindingCellular componentcytoplasm centrosome cell projection cyclin dependent protein kinase holoenzyme complex ruffle microtubule organizing center cytoskeleton nucleus cytosol nucleoplasm cyclin D2 CDK6 complexBiological processcell differentiation lateral ventricle development phosphorylation positive regulation of cell matrix adhesion positive regulation of fibroblast proliferation dentate gyrus development regulation of erythrocyte differentiation astrocyte development negative regulation of cell differentiation response to virus negative regulation of cell cycle negative regulation of osteoblast differentiation generation of neurons cell division regulation of cell motility protein phosphorylation negative regulation of epithelial cell proliferation regulation of gene expression cell cycle type B pancreatic cell development negative regulation of myeloid cell differentiation negative regulation of cellular senescence gliogenesis negative regulation of cell population proliferation negative regulation of monocyte differentiation signal transduction regulation of G2 M transition of mitotic cell cycle regulation of cell population proliferation cell dedifferentiation G1 S transition of mitotic cell cycle negative regulation of transcription by RNA polymerase II hematopoietic progenitor cell differentiation Notch signaling pathway positive regulation of gene expression hemopoiesis T cell differentiation in thymus hematopoietic stem cell differentiation regulation of hematopoietic stem cell differentiation negative regulation of G1 S transition of mitotic cell cycleSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez102112571EnsemblENSG00000105810ENSMUSG00000040274UniProtQ00534Q64261RefSeq mRNA NM 001145306NM 001259NM 009873RefSeq protein NP 001138778NP 001250NP 034003Location UCSC Chr 7 92 6 92 84 MbChr 5 3 39 3 58 MbPubMed search 3 4 WikidataView Edit HumanView Edit MouseThis kinase is a catalytic subunit of the protein kinase complex important for the G1 phase progression and G1 S transition of the cell cycle and the complex is composed also by an activating sub unit the cyclin D 10 The activity of this kinase first appears in mid G1 phase which is controlled by the regulatory subunits including D type cyclins and members of INK4 family of CDK inhibitors 7 This kinase as well as CDK4 has been shown to phosphorylate and thus regulate the activity of tumor suppressor Retinoblastoma protein making CDK6 an important protein in cancer development 10 Contents 1 Structure 2 Function 2 1 Cell cycle 2 2 Cellular development 2 3 DNA protection 2 4 Metabolic homeostasis 2 5 Centrosome stability 3 Mechanisms of regulation 4 Clinical relevance 4 1 Cancer 4 2 Medulloblastoma 4 3 As a drug target 4 4 Interactions 5 See also 6 References 7 Further reading 8 External linksStructure EditThe CDK6 gene is conserved in eukaryotes including the budding yeast and the nematode Caenorhabditis elegans 11 The CDK6 gene is located on chromosome 7 in humans The gene spans 231 706 base pairs and encodes a 326 amino acid protein with a kinase function 6 The gene is overexpressed in cancers like lymphoma leukemia medulloblastoma and melanoma associated with chromosomal rearrangements 6 The CDK6 protein contains a catalytic core composed of a serine threonine domain 12 This protein also contains an ATP binding pocket inhibitory and activating phosphorylation sites a PSTAIRE like cyclin binding domain and an activating T loop motif 10 After binding the Cyclin in the PSTAIRE helix the protein changes its conformational structure to expose the phosphorylation motif 10 The protein can be found in the cytoplasm and the nucleus however most of the active complexes are found in the nucleus of proliferating cells 10 Function EditCell cycle Edit In 1994 Matthew Meyerson and Ed Harlow investigated the product of a close analogous gene of CDK4 7 This gene identified as PLSTIRE was translated into a protein that interacted with the cyclins CD1 CD2 and CD3 same as CDK4 but that was different from CDK4 the protein was then renamed CDK6 for simplicity 7 In mammalian cells cell cycle is activated by CDK6 in the early G1 phase 13 through interactions with cyclins D1 D2 and D3 7 There are many changes in gene expression that are regulated through this enzyme 14 After the complex is formed the C CDK6 enzymatic complex phosphorylates the protein pRb 15 After its phosphorylation pRb releases its binding partner E2F a transcriptional activator which in turn activates DNA replication 16 The CDK6 complex ensures a point of switch to commit to division responding to external signals like mitogens and growth factors 17 CDK6 is involved in a positive feedback loop that activates transcription factors through a reaction cascade 18 Importantly these C CDK complexes act as a kinase phosphorylating and inactivating the protein of Rb and p Rb related pocket proteins p107 and p130 19 While doing this the CDK6 in conjunction with CDK4 act as a switch signal that first appears in G1 7 directing the cell towards S phase of the cell cycle 14 CDK6 is important for the control of G1 to S phase transition 7 However in recent years new evidence proved that the presence of CDK6 is not essential for proliferation in every cell type 20 the cell cycle has a complex circuitry of regulation and the role of CDK6 might be more important in certain cell types than in others where CDK4 or CDK2 can act as protein kinases compensating its role 20 21 Cellular development Edit In mutant Knockout mice of CDK6 the hematopoietic function is impaired regardless of otherwise organism normal development 20 This might hint additional roles of CDK6 in the development of blood components 20 There are additional functions of CDK6 not associated with its kinase activity 22 For example CDK6 is involved in the differentiation of T cells acting as an inhibitor of differentiation 22 Even though CDK6 and CDK4 share 71 amino acid identity this role in differentiation is unique to CDK6 22 CDK6 has also been found to be important in the development of other cell lines for example CDK6 has a role in the alteration of the morphology of astrocytes 23 and in the development of other stem cells 10 16 DNA protection Edit CDK6 differs from CDK4 in other important roles 24 For example CDK6 plays a role in the accumulation of the apoptosis proteins p53 and p130 this accumulation keeps cells from entering cell division if there is DNA damage activating pro apoptotic pathways 24 Metabolic homeostasis Edit Studies in the metabolic control of cells have revealed yet another role of CDK6 25 This new role is associated with the balance of the oxidative and non oxidative branches of the pentose pathway in cells 25 This pathway is a known route altered in cancer cells when there is an aberrant overexpression of CDK6 and CDK4 25 The overexpression of these proteins provides the cancer cells with a new hallmark capability of cancer the deregulation of the cell metabolism 25 Centrosome stability Edit In 2013 researchers discovered yet another role of CDK6 26 There is evidence that CDK6 associates with the centrosome and controls organized division and cell cycle phases in neuron production 26 When the CDK6 gene is mutated in these developing lines the centrosomes are not properly divided this could lead to division problems such as aneuploidy which in turns leads to health issues like primary microcephaly 26 Mechanisms of regulation EditCDK6 is positively regulated primarily by its union to the D cyclins D1 D2 and D3 If this subunit of the complex is not available CDK6 is not active or available to phosphorylate the Rb substrate 9 An additional positive activator needed by CDK6 is the phosphorylation in a conserved threonine residue located in 177 position this phosphorylation is done by the cdk activating kinases CAK 27 Additionally CDK6 can be phosphorylated and activated by the Kaposi s sarcoma associated herpes virus stimulating the CDK6 over activation and uncontrolled cell proliferation 28 CDK6 is negatively regulated by binding to certain inhibitors that can be classified in two groups 29 CKIs or CIP KIP family members like the protein p21 16 and p27 act blocking and inhibiting the assembled C CDKs binding complex enzymes 27 in their catalytic domain 30 Furthermore inhibitors of the INK4 family members like p15 p16 p18 and p19 inhibit the monomer of CDK6 preventing the complex formation 19 31 Clinical relevance EditCDK6 is a protein kinase activating cell proliferation it is involved in an important point of restriction in the cell cycle 18 For this reason CDK6 and other regulators of the G1 phase of the cell cycle are known to be unbalanced in more than 80 90 of tumors 9 In cervical cancer cells CDK6 function has been shown to be altered indirectly by the p16 inhibitor 31 CDK6 is also overexpressed in tumors that exhibit drug resistance for example glioma malignancies exhibit resistance to chemotherapy using temozolomide TMZ when they have a mutation overexpressing CDK6 32 Likewise the overexpression of CDK6 is also associated with resistance to hormone therapy using the anti oestrogen Fluvestrant in breast cancer 33 Cancer Edit Loss of normal cell cycle control is the first step to developing different hallmarks of cancer alterations of CDK6 can directly or indirectly affect the following hallmarks disregulated cell cellular energetics sustaining of proliferative signaling evading growth suppressors and inducing angiogenesis 9 for example deregulation of CDK6 has been shown to be important in lymphoid malignancies by increasing angiogenesis a hallmark of cancer 19 These features are reached through upregulation of CDK6 due to chromosome alterations or epigenetic dysregulations 9 Additionally CDK6 might be altered through genomic instability a mechanism of downregulation of tumor suppressor genes this represents another evolving hallmark of cancer 34 Medulloblastoma Edit Medulloblastoma is the most common cause of brain cancer in children 35 About a third of these cancers have upregulated CDK6 representing a marker for poor prognosis for this disease 35 Since it is so common for these cells to have alterations in CDK6 researchers are seeking for ways to downregulate CDK6 expression acting specifically in those cell lines The MicroRNA miR 124 has successfully controlled cancer progression in an in vitro setting for medulloblastoma and glioblastoma cells 35 Furthermore researchers have found that it successfully reduces the growth of xenograft tumors in rat models 35 As a drug target Edit Further information CDK inhibitor The direct targeting of CDK6 and CDK4 should be used with caution in the treatment of cancer because these enzymes are important for the cell cycle of normal cells as well 35 Furthermore small molecules targeting these proteins might increase drug resistance events 35 However these kinases have been shown to be useful as coadjuvants in breast cancer chemotherapy 36 Another indirect mechanism for the control of CDK6 expression is the use of a mutated D cyclin that binds with high affinity to CDK6 but does not induce its kinase activity 36 this mechanism was studied in the development of mammary tumorigenesis in rat cells however the clinical effects have not yet been shown in human patients 36 A Interactions Edit Cyclin dependent kinase 6 interacts with CDKN2C 37 38 39 Cyclin D1 40 41 Cyclin D3 40 42 P16 43 44 45 PPM1B 46 and PPP2CA 46 See also EditCell cycle Cyclin dependent kinase Cyclin dependent kinase 4 Mitosis The Hallmarks of CancerReferences Edit a b c GRCh38 Ensembl release 89 ENSG00000105810 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000040274 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Meyerson M Enders GH Wu CL Su LK Gorka C Nelson C Harlow E Tsai LH Aug 1992 A family of human cdc2 related protein kinases The EMBO Journal 11 8 2909 17 doi 10 1002 j 1460 2075 1992 tb05360 x PMC 556772 PMID 1639063 a b c Entrez Gene CDK6 cyclin dependent kinase 6 a b c d e f g Meyerson M Harlow E 1994 Identification of G1 Kinase Activity for cdk6 a Novel Cyclin D Partner Molecular and Cellular Biology 14 3 2077 86 doi 10 1128 MCB 14 3 2077 PMC 358568 PMID 8114739 Robbins Basic Pathology by Vinay Kumar Abul K Abbas and Jon C Aster eBook on accessed April 21 2014 https www inkling com store book robbins basic pathology kumar abbas aster 9th chapterId d0de80fcb2d4401c91c3045fcf0f45e1 a b c d e Diaz Moralli S Tarrado Castellarnau M Miranda A Cascante M May 2013 Targeting cell cycle regulation in cancer therapy Pharmacology amp Therapeutics 138 2 255 71 doi 10 1016 j pharmthera 2013 01 011 PMID 23356980 a b c d e f Lim S Kaldis P Aug 2013 Cdks cyclins and CKIs roles beyond cell cycle regulation Development 140 15 3079 93 doi 10 1242 dev 091744 PMID 23861057 Liu Ji Kipreos Edward T 2000 Evolution of Cyclin Dependent Kinases CDKs and CDK Activating Kinases CAKs Differential Conservation of CAKs in Yeast and Metazoa Molecular Biology and Evolution 17 7 1061 74 doi 10 1093 oxfordjournals molbev a026387 PMID 10889219 Reinhardt HC Yaffe MB Sep 2013 Phospho Ser Thr binding domains navigating the cell cycle and DNA damage response Nature Reviews Molecular Cell Biology 14 9 563 80 doi 10 1038 nrm3640 PMID 23969844 S2CID 149598 Harvey Lodish et al Molecular Cell Biology 4th Edition 2000 https www ncbi nlm nih gov books NBK21497 a b Bertoli C Skotheim JM de Bruin RA Aug 2013 Control of cell cycle transcription during G1 and S phases Nature Reviews Molecular Cell Biology 14 8 518 28 doi 10 1038 nrm3629 PMC 4569015 PMID 23877564 Ezhevsky SA Ho A Becker Hapak M Davis PK Dowdy SF Jul 2001 Differential regulation of retinoblastoma tumor suppressor protein by G 1 cyclin dependent kinase complexes in vivo Molecular and Cellular Biology 21 14 4773 84 doi 10 1128 MCB 21 14 4773 4784 2001 PMC 87164 PMID 11416152 a b c Grossel MJ Hinds PW Feb 2006 Beyond the cell cycle a new role for Cdk6 in differentiation Journal of Cellular Biochemistry 97 3 485 93 doi 10 1002 jcb 20712 PMID 16294322 S2CID 41684216 Bartek J Lukas J 2001 Mammalian G1 and S Phase Checkpoints in Response to DNA Damage Current Opinion in Cell Biology 13 6 738 47 doi 10 1016 s0955 0674 00 00280 5 PMID 11698191 a b Aarts M Linardopoulos S Turner NC Aug 2013 Tumour selective targeting of cell cycle kinases for cancer treatment Current Opinion in Pharmacology 13 4 529 35 doi 10 1016 j coph 2013 03 012 PMID 23597425 a b c Kollmann K Heller G Schneckenleithner C Warsch W Scheicher R Ott RG Schafer M Fajmann S Schlederer M Schiefer AI Reichart U Mayerhofer M Hoeller C Zochbauer Muller S Kerjaschki D Bock C Kenner L Hoefler G Freissmuth M Green AR Moriggl R Busslinger M Malumbres M Sexl V Aug 2013 A kinase independent function of CDK6 links the cell cycle to tumor angiogenesis Cancer Cell 24 2 167 81 doi 10 1016 j ccr 2013 07 012 PMC 3743049 PMID 23948297 a b c d Katarzyna Kozar and Piotr Sicinski Cell Cycle Progression without Cyclin D CDK4 and Cyclin D CDK6 Complexes Cell Cycle 4 no 3 March 2005 388 91 Malumbres M Sotillo R Santamaria D Galan J Cerezo A Ortega S Dubus P Barbacid M Aug 2004 Mammalian cells cycle without the D type cyclin dependent kinases Cdk4 and Cdk6 Cell 118 4 493 504 doi 10 1016 j cell 2004 08 002 PMID 15315761 S2CID 13371605 a b c Martha J Grossel and Philip W Hinds From Cell Cycle to Differentiation An Expanding Role for cdk6 Cell Cycle 5 no 3 February 2006 266 70 Ericson Karen K et al 2003 Expression of Cyclin Dependent Kinase 6 but Not Cyclin Dependent Kinase 4 Alters Morphology of Cultured Mouse Astrocytes11NSF under CAREER Grant 9984454 to Martha J Grossel Molecular Cancer Research 1 9 654 64 a b Nagasawa M Gelfand EW Lucas JJ May 2001 Accumulation of high levels of the p53 and p130 growth suppressing proteins in cell lines stably over expressing cyclin dependent kinase 6 cdk6 Oncogene 20 23 2889 99 doi 10 1038 sj onc 1204396 PMID 11420701 a b c d Zanuy M Ramos Montoya A Villacanas O Canela N Miranda A Aguilar E Agell N Bachs O Rubio Martinez J Pujol MD Lee WN Marin S Cascante M Jun 2012 Cyclin dependent kinases 4 and 6 control tumor progression and direct glucose oxidation in the pentose cycle Metabolomics 8 3 454 64 doi 10 1007 s11306 011 0328 x PMC 3361763 PMID 22661920 a b c Hussain Muhammad S et al 2013 CDK6 Associates with the Centrosome during Mitosis and Is Mutated in a Large Pakistani Family with Primary Microcephaly Human Molecular Genetics 22 25 5199 5214 doi 10 1093 hmg ddt374 PMID 23918663 a b LaBaer J et al 1997 New Functional Activities for the p21 Family of CDK Inhibitors Genes amp Development 11 7 847 62 doi 10 1101 gad 11 7 847 PMID 9106657 Kaldis P Mar 2005 The N terminal peptide of the Kaposi s sarcoma associated herpesvirus KSHV cyclin determines substrate specificity The Journal of Biological Chemistry 280 12 11165 74 doi 10 1074 jbc M408887200 PMID 15664993 Nurse P 2000 A Long Twentieth Century of the Cell Cycle and beyond Cell 100 1 71 78 doi 10 1016 s0092 8674 00 81684 0 PMID 10647932 S2CID 16366539 Bockstaele L Kooken H Libert F Paternot S Dumont JE de Launoit Y Roger PP Coulonval K Jul 2006 Regulated activating Thr172 phosphorylation of cyclin dependent kinase 4 CDK4 its relationship with cyclins and CDK inhibitors Molecular and Cellular Biology 26 13 5070 85 doi 10 1128 MCB 02006 05 PMC 1489149 PMID 16782892 a b Khleif S N et al 1996 Inhibition of Cyclin D CDK4 CDK6 Activity Is Associated with an E2F Mediated Induction of Cyclin Kinase Inhibitor Activity Proceedings of the National Academy of Sciences of the United States of America 93 9 4350 54 Bibcode 1996PNAS 93 4350K doi 10 1073 pnas 93 9 4350 PMC 39540 PMID 8633069 Li B He H Tao BB Zhao ZY Hu GH Luo C Chen JX Ding XH Sheng P Dong Y Zhang L Lu YC Sep 2012 Knockdown of CDK6 enhances glioma sensitivity to chemotherapy Oncology Reports 28 3 909 14 doi 10 3892 or 2012 1884 PMID 22736304 Giessrigl B Schmidt WM Kalipciyan M Jeitler M Bilban M Gollinger M Krieger S Jager W Mader RM Krupitza G Nov 2013 Fulvestrant induces resistance by modulating GPER and CDK6 expression implication of methyltransferases deacetylases and the hSWI SNF chromatin remodelling complex British Journal of Cancer 109 10 2751 62 doi 10 1038 bjc 2013 583 PMC 3833203 PMID 24169358 Negrini S Gorgoulis VG Halazonetis TD Mar 2010 Genomic instability an evolving hallmark of cancer Nature Reviews Molecular Cell Biology 11 3 220 28 doi 10 1038 nrm2858 PMID 20177397 S2CID 10217969 a b c d e f Silber J Hashizume R Felix T Hariono S Yu M Berger MS Huse JT VandenBerg SR James CD Hodgson JG Gupta N Jan 2013 Expression of miR 124 inhibits growth of medulloblastoma cells Neuro Oncology 15 1 83 90 doi 10 1093 neuonc nos281 PMC 3534424 PMID 23172372 a b c Landis MW Pawlyk BS Li T Sicinski P Hinds PW Jan 2006 Cyclin D1 dependent kinase activity in murine development and mammary tumorigenesis Cancer Cell 9 1 13 22 doi 10 1016 j ccr 2005 12 019 PMID 16413468 Ewing RM Chu P Elisma F Li H Taylor P Climie S McBroom Cerajewski L Robinson MD O Connor L Li M Taylor R Dharsee M Ho Y Heilbut A Moore L Zhang S Ornatsky O Bukhman YV Ethier M Sheng Y Vasilescu J Abu Farha M Lambert JP Duewel HS Stewart II Kuehl B Hogue K Colwill K Gladwish K Muskat B Kinach R Adams SL Moran MF Morin GB Topaloglou T Figeys D 2007 Large scale mapping of human protein protein interactions by mass spectrometry Molecular Systems Biology 3 89 doi 10 1038 msb4100134 PMC 1847948 PMID 17353931 Guan KL Jenkins CW Li Y Nichols MA Wu X O Keefe CL Matera AG Xiong Y Dec 1994 Growth suppression by p18 a p16INK4 MTS1 and p14INK4B MTS2 related CDK6 inhibitor correlates with wild type pRb function Genes amp Development 8 24 2939 52 doi 10 1101 gad 8 24 2939 PMID 8001816 Jeffrey PD Tong L Pavletich NP Dec 2000 Structural basis of inhibition of CDK cyclin complexes by INK4 inhibitors Genes amp Development 14 24 3115 25 doi 10 1101 gad 851100 PMC 317144 PMID 11124804 a b Lin J Jinno S Okayama H Apr 2001 Cdk6 cyclin D3 complex evades inhibition by inhibitor proteins and uniquely controls cell s proliferation competence Oncogene 20 16 2000 9 doi 10 1038 sj onc 1204375 PMID 11360184 Sugimoto M Nakamura T Ohtani N Hampson L Hampson IN Shimamoto A Furuichi Y Okumura K Niwa S Taya Y Hara E Nov 1999 Regulation of CDK4 activity by a novel CDK4 binding protein p34 SEI 1 Genes amp Development 13 22 3027 33 doi 10 1101 gad 13 22 3027 PMC 317153 PMID 10580009 Meyerson M Harlow E Mar 1994 Identification of G1 kinase activity for cdk6 a novel cyclin D partner Molecular and Cellular Biology 14 3 2077 86 doi 10 1128 MCB 14 3 2077 PMC 358568 PMID 8114739 Fahraeus R Paramio JM Ball KL Lain S Lane DP Jan 1996 Inhibition of pRb phosphorylation and cell cycle progression by a 20 residue peptide derived from p16CDKN2 INK4A PDF Current Biology 6 1 84 91 doi 10 1016 s0960 9822 02 00425 6 PMID 8805225 S2CID 23024663 Russo AA Tong L Lee JO Jeffrey PD Pavletich NP Sep 1998 Structural basis for inhibition of the cyclin dependent kinase Cdk6 by the tumour suppressor p16INK4a Nature 395 6699 237 43 Bibcode 1998Natur 395 237R doi 10 1038 26155 PMID 9751050 S2CID 204997058 Kaldis P Ojala PM Tong L Makela TP Solomon MJ Dec 2001 CAK independent activation of CDK6 by a viral cyclin Molecular Biology of the Cell 12 12 3987 99 doi 10 1091 mbc 12 12 3987 PMC 60770 PMID 11739795 a b Cheng A Kaldis P Solomon MJ Nov 2000 Dephosphorylation of human cyclin dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms The Journal of Biological Chemistry 275 44 34744 9 doi 10 1074 jbc M006210200 PMID 10934208 Further reading EditAdams MD Kerlavage AR Fleischmann RD Fuldner RA Bult CJ Lee NH Kirkness EF Weinstock KG Gocayne JD White O Sep 1995 Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence PDF Nature 377 6547 Suppl 3 174 PMID 7566098 Aprelikova O Xiong Y Liu ET Aug 1995 Both p16 and p21 families of cyclin dependent kinase CDK inhibitors block the phosphorylation of cyclin dependent kinases by the CDK activating kinase The Journal of Biological Chemistry 270 31 18195 7 doi 10 1074 jbc 270 31 18195 PMID 7629134 Lucas JJ Szepesi A Modiano JF Domenico J Gelfand EW Jun 1995 Regulation of synthesis and activity of the PLSTIRE protein cyclin dependent kinase 6 cdk6 a major cyclin D associated cdk4 homologue in normal human T lymphocytes Journal of Immunology 154 12 6275 84 PMID 7759865 Bullrich F MacLachlan TK Sang N Druck T Veronese ML Allen SL Chiorazzi N Koff A Heubner K Croce CM Mar 1995 Chromosomal mapping of members of the cdc2 family of protein kinases cdk3 cdk6 PISSLRE and PITALRE and a cdk inhibitor p27Kip1 to regions involved in human cancer Cancer Research 55 6 1199 205 PMID 7882308 Guan KL Jenkins CW Li Y Nichols MA Wu X O Keefe CL Matera AG Xiong Y Dec 1994 Growth suppression by p18 a p16INK4 MTS1 and p14INK4B MTS2 related CDK6 inhibitor correlates with wild type pRb function Genes amp Development 8 24 2939 52 doi 10 1101 gad 8 24 2939 PMID 8001816 Meyerson M Harlow E Mar 1994 Identification of G1 kinase activity for cdk6 a novel cyclin D partner Molecular and Cellular Biology 14 3 2077 86 doi 10 1128 MCB 14 3 2077 PMC 358568 PMID 8114739 Fahraeus R Paramio JM Ball KL Lain S Lane DP Jan 1996 Inhibition of pRb phosphorylation and cell cycle progression by a 20 residue peptide derived from p16CDKN2 INK4A PDF Current Biology 6 1 84 91 doi 10 1016 S0960 9822 02 00425 6 PMID 8805225 S2CID 23024663 Bonaldo MF Lennon G Soares MB Sep 1996 Normalization and subtraction two approaches to facilitate gene discovery Genome Research 6 9 791 806 doi 10 1101 gr 6 9 791 PMID 8889548 Lamphere L Fiore F Xu X Brizuela L Keezer S Sardet C Draetta GF Gyuris J Apr 1997 Interaction between Cdc37 and Cdk4 in human cells Oncogene 14 16 1999 2004 doi 10 1038 sj onc 1201036 PMID 9150368 Nagasawa M Melamed I Kupfer A Gelfand EW Lucas JJ Jun 1997 Rapid nuclear translocation and increased activity of cyclin dependent kinase 6 after T cell activation Journal of Immunology 158 11 5146 54 PMID 9164930 Ezhevsky SA Nagahara H Vocero Akbani AM Gius DR Wei MC Dowdy SF Sep 1997 Hypo phosphorylation of the retinoblastoma protein pRb by cyclin D Cdk4 6 complexes results in active pRb Proceedings of the National Academy of Sciences of the United States of America 94 20 10699 704 Bibcode 1997PNAS 9410699E doi 10 1073 pnas 94 20 10699 PMC 23451 PMID 9380698 Fahraeus R Lain S Ball KL Lane DP Feb 1998 Characterization of the cyclin dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule Oncogene 16 5 587 96 doi 10 1038 sj onc 1201580 PMID 9482104 Gonzales AJ Goldsworthy TL Fox TR Jun 1998 Chemical transformation of mouse liver cells results in altered cyclin D CDK protein complexes Carcinogenesis 19 6 1093 102 doi 10 1093 carcin 19 6 1093 PMID 9667749 Russo AA Tong L Lee JO Jeffrey PD Pavletich NP Sep 1998 Structural basis for inhibition of the cyclin dependent kinase Cdk6 by the tumour suppressor p16INK4a Nature 395 6699 237 43 Bibcode 1998Natur 395 237R doi 10 1038 26155 PMID 9751050 S2CID 204997058 Brotherton DH Dhanaraj V Wick S Brizuela L Domaille PJ Volyanik E Xu X Parisini E Smith BO Archer SJ Serrano M Brenner SL Blundell TL Laue ED Sep 1998 Crystal structure of the complex of the cyclin D dependent kinase Cdk6 bound to the cell cycle inhibitor p19INK4d Nature 395 6699 244 50 Bibcode 1998Natur 395 244B doi 10 1038 26164 PMID 9751051 S2CID 13337394 Jiang W Wells NJ Hunter T May 1999 Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6 Proceedings of the National Academy of Sciences of the United States of America 96 11 6193 8 Bibcode 1999PNAS 96 6193J doi 10 1073 pnas 96 11 6193 PMC 26858 PMID 10339564 Yarbrough WG Buckmire RA Bessho M Liu ET Sep 1999 Biologic and biochemical analyses of p16 INK4a mutations from primary tumors Journal of the National Cancer Institute 91 18 1569 74 doi 10 1093 jnci 91 18 1569 PMID 10491434 Harbour JW Luo RX Dei Santi A Postigo AA Dean DC Sep 1999 Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1 Cell 98 6 859 69 doi 10 1016 S0092 8674 00 81519 6 PMID 10499802 S2CID 14025897 Grossel MJ Baker GL Hinds PW Oct 1999 cdk6 can shorten G 1 phase dependent upon the N terminal INK4 interaction domain The Journal of Biological Chemistry 274 42 29960 7 doi 10 1074 jbc 274 42 29960 PMID 10514479 External links EditCyclin Dependent Kinase 6 at the US National Library of Medicine Medical Subject Headings MeSH CDK6 human gene location in the UCSC Genome Browser CDK6 human gene details in the UCSC Genome Browser Genecards UniProt Portal Biology Retrieved from https en wikipedia org w index php title Cyclin dependent kinase 6 amp oldid 1103384357, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.