Cyclin-dependent kinase 6

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Cyclin-dependent kinase 6
Protein CDK6 PDB 1bi7.png
PDB rendering based on 1bi7.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CDK6 ; MCPH12; PLSTIRE
External IDs OMIM603368 MGI1277162 HomoloGene963 ChEMBL: 2508 GeneCards: CDK6 Gene
EC number 2.7.11.22
RNA expression pattern
PBB GE CDK6 207143 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1021 12571
Ensembl ENSG00000105810 ENSMUSG00000040274
UniProt Q00534 Q64261
RefSeq (mRNA) NM_001145306 NM_009873
RefSeq (protein) NP_001138778 NP_034003
Location (UCSC) Chr 7:
92.6 – 92.84 Mb
Chr 5:
3.34 – 3.53 Mb
PubMed search [1] [2]

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene.[1][2] It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins.[3] The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4.[4] 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.[5]

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.[6] 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.[3] 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.[6]

Structure[edit]

The CDK6 gene is conserved in eukaryotes, including the budding yeast and the nematode Caenorhabditis elegans.[7] The CDK6 gene is located in the chromosome 7 in humans, it is encoded by 231,706 base pairs and is translated to a 326 amino acid protein with a kinase function.[2] The gene is over expressed in cancers like lymphoma, leukemia, medulloblastoma and melanoma associated with chromosomal rearrangements.[2] The CDK6 protein contains a catalytic core composed of a serine/threonine domain.[8] 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.[6] After binding the Cyclin in the PSTAIRE helix, the protein changes its conformational structure to expose the phosphorylation motif.[6] 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.[6]

Function[edit]

Cell cycle[edit]

In 1994, Matthew Meyerson and Ed Harlow investigated the product of a close analogous gene of CDK4.[3] 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.[3] In mammalian cells, cell cycle is activated by CDK6 in the early G1 phase[9] through interactions with cyclins D1, D2 and D3.[3] There are many changes in gene expression that are regulated through this enzymes.[10] After the complex is formed, the C-CDK6 enzymatic complex phosphorylates the protein pRb.[11] After its phosphorylation, pRb releases its binding partner E2F, a transcriptional activator, which in turns activate DNA replication.[12] The CDK6 complex ensures a point of switch to commit to division responding to external signals, like mitogens and growth factors.[13]

CDK6 is involved in a positive feedback loop that activates transcription factors through a reaction cascade.[14] Importantly, these C-DCK complexes act as a kinase, phosphorylating and inactivating the protein of Rb and p-Rb related “pocket proteins” p107 and p130.[15] While doing this, the CDK6 in conjunction with CDK4, act as a switch signal that first appears in G1,[3] directing the cell towards S phase of the cell cycle.[10]

CDK6 is important for the control of G1 to S phase transition.[3] However, in recent years, new evidence proved that the presence of CDK6 is not essential for proliferation in every cell type,[16] 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.[16][17]

Cellular development[edit]

In mutant Knockout mice of CDK6, the hematopoietic function is impaired, regardless of otherwise organism normal development.[16] This might hint additional roles of CDK6 in the development of blood components.[16] There are additional functions of CDK6 not associated with its kinase activity.[18] For example, CDK6 is involved in the differentiation of T cells, acting as an inhibitor of differentiation.[18] Even though CDK6 and CDK4 share 71% amino acid identity, this role in differentiation is unique to CDK6.[18] 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[19] and in the development of other stem cells.[6][12]

DNA protection[edit]

CDK6 differs from CDK4 in other important roles.[20] For example, CDK6 plays a role in the accumulation of the apoptosis proteins p53 and p130, this accumulation avoids cells from entering cell division if there is DNA damage, activating pro- apoptotic pathways.[20]

Metabolic homeostasis[edit]

Studies in the metabolic control of cells have revealed yet another role of CDK6.[21] This new role is associated with the balance of the oxidative and non-oxidative branches of the pentose pathway in cells.[21] This pathway is a known route altered in cancer cells, when there is an aberrant overexpression of CDK6 and CDK4.[21] The overepression of these proteins provides the cancer cells with a new hallmark capability of cancer; the deregulation of the cell metabolism.[21]

Centrosome stability[edit]

In 2013 researches discovered yet another additional role of CDK6.[22] There is evidence that CDK6 associates with the centrosome and controls organized division and cell cycle phases in neuron production.[22] 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.[22]

Mechanisms of regulation[edit]

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 pRb substrate.[5] 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.[23] Additionally, CDK6 can be phosphorylated and activated by the Kaposi's sarcoma-associated herpes virus, stimulating the CDK6 over activation and uncontrolled cell proliferation.[24]

CDK6 is negatively regulated by binding to certain inhibitors that can be classified in two groups;[25] CKIs or CIP/KIP family members like the protein p21[12] and p27 act blocking and inhibiting the assembled C-CDKs binding complex enzymes[23] in their catalytic domain.[26]

Furthermore, inhibitors of the INK4 family members like p15, p16, p18 and p19 inhibit the monomer of CDK6, preventing the complex formation.[15][27]

Clinical relevance[edit]

CDK6 is a protein kinase activating cell proliferation, it is involved in an important point of restriction in the cell cycle.[14] 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.[5] In cervical cancer cells, CDK6 function has been shown to be altered indirectly by the p16 inhibitor.[27] 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.[28] Likewise, the overexpression of CDK6 is also associated with resistance to hormone therapy using the anti oestrogen Fluvestrant in breast cancer.[29]

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,[5] for example, deregulation of CDK6 has been shown to be important in lymphoid malignancies by increasing angiogenesis, a hallmark of cancer.[15] These features are reached through upregulation of CDK6 due to chromosome alterations or epigenetic dysregulations.[5] Additionally, CDK6 might be altered through genomic instability, a mechanism of downregulation of tumor suppressor genes; this represents another evolving hallmark of cancer.[30]

Medulloblastoma[edit]

Medulloblastoma is the most common cause of brain cancer in children.[31] About a third of these cancers have upregulated CDK6, representing a marker for poor prognosis for this disease.[31] 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.[31] Furthermore, researchers have found that it successfully reduces the growth of xenograft tumors in rat models.[31]

As a drug target[edit]

The direct targeting of CDK6 and CDK4 should be used with caution in the treatment of cancer, the reason why is because these enzymes are important for the cell cycle of normal cells we well.[31] Furthermore, small molecules targeting these proteins might increase drug resistance events.[31] However, these kinases have been shown to be useful as coadjuvants in breast cancer chemotherapy.[32] 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.[32] 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.[32] As of 2014, different drugs to target these type of kinases have been developed, however none of those have been yet approved for the treatment of human cancers by the FDA.[33] Inhibitors of CDK6 have shown the disadvantage of not being specific in the union to the CDK6, and as a consequence they might act inhibiting other CDKs that are crucial in other tissues and at other points of cell cycle.[33] The compound PD-0332991, is currently under more than 20 clinical trials acting either as single agent or as coadjuvant of other therapies in clinical trial phase I-III showing promising results in the control of breast cancer in-vitro.[34]

Interactions[edit]

Cyclin-dependent kinase 6 interacts with:

See also[edit]

Cell cycle, Mitosis, CDK, CDK4, Hallmarks of cancer Genecards Uniprot NCI

References[edit]

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  37. ^ 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. 
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Further reading[edit]

  • 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. 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". Current Biology 6 (1): 84–91. doi:10.1016/S0960-9822(02)00425-6. PMID 8805225. 
  • 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. 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. doi:10.1038/26155. PMID 9751050. 
  • 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. doi:10.1038/26164. PMID 9751051. 
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