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{{STRUCTURE_1bi7|  PDB=1bi7  |  SCENE=  }}
===MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX===
{{ABSTRACT_PUBMED_9751050}}


==Disease==
==MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX==
[[http://www.uniprot.org/uniprot/CD2A1_HUMAN CD2A1_HUMAN]] Note=The association between cutaneous and uveal melanomas in some families suggests that mutations in CDKN2A may account for a proportion of uveal melanomas. However, CDKN2A mutations are rarely found in uveal melanoma patients.  Defects in CDKN2A are the cause of cutaneous malignant melanoma type 2 (CMM2) [MIM:[http://omim.org/entry/155601 155601]]. Malignant melanoma is a malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but also may involve other sites.<ref>PMID:7987387</ref><ref>PMID:8595405</ref><ref>PMID:8653684</ref><ref>PMID:8710906</ref><ref>PMID:9328469</ref><ref>PMID:9425228</ref><ref>PMID:10651484</ref><ref>PMID:11506491</ref><ref>PMID:12019208</ref><ref>PMID:10874641</ref><ref>PMID:14646619</ref><ref>PMID:19260062</ref> Defects in CDKN2A are the cause of familial atypical multiple mole melanoma-pancreatic carcinoma syndrome (FAMMMPC) [MIM:[http://omim.org/entry/606719 606719]].  Defects in CDKN2A are a cause of Li-Fraumeni syndrome (LFS) [MIM:[http://omim.org/entry/151623 151623]]. LFS is a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53.<ref>PMID:10484981</ref>  Defects in CDKN2A are the cause of melanoma-astrocytoma syndrome (MASTS) [MIM:[http://omim.org/entry/155755 155755]]. The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumors, commonly astrocytoma.<ref>PMID:11136714</ref>  
<StructureSection load='1bi7' size='340' side='right'caption='[[1bi7]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
 
== Structural highlights ==
==Function==
<table><tr><td colspan='2'>[[1bi7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BI7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1BI7 FirstGlance]. <br>
[[http://www.uniprot.org/uniprot/CDK6_HUMAN CDK6_HUMAN]] Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans.<ref>PMID:8114739</ref><ref>PMID:12833137</ref><ref>PMID:14985467</ref><ref>PMID:15254224</ref><ref>PMID:15809340</ref><ref>PMID:17431401</ref><ref>PMID:17420273</ref><ref>PMID:20668294</ref><ref>PMID:20333249</ref> [[http://www.uniprot.org/uniprot/CD2A1_HUMAN CD2A1_HUMAN]] Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein.<ref>PMID:7972006</ref><ref>PMID:16782892</ref>  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.4&#8491;</td></tr>
 
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1bi7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bi7 OCA], [https://pdbe.org/1bi7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1bi7 RCSB], [https://www.ebi.ac.uk/pdbsum/1bi7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1bi7 ProSAT]</span></td></tr>
==About this Structure==
</table>
[[1bi7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1BI7 OCA].  
== Function ==
[https://www.uniprot.org/uniprot/CDK6_HUMAN CDK6_HUMAN] Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans.<ref>PMID:8114739</ref> <ref>PMID:12833137</ref> <ref>PMID:14985467</ref> <ref>PMID:15254224</ref> <ref>PMID:15809340</ref> <ref>PMID:17431401</ref> <ref>PMID:17420273</ref> <ref>PMID:20668294</ref> <ref>PMID:20333249</ref>  
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bi/1bi7_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1bi7 ConSurf].
<div style="clear:both"></div>


==See Also==
==See Also==
*[[Cyclin-dependent kinase|Cyclin-dependent kinase]]
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:009751050</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Jeffrey, P D.]]
[[Category: Large Structures]]
[[Category: Lee, J O.]]
[[Category: Jeffrey PD]]
[[Category: Pavletich, N P.]]
[[Category: Lee JO]]
[[Category: Russo, A A.]]
[[Category: Pavletich NP]]
[[Category: Tong, L.]]
[[Category: Russo AA]]
[[Category: Cdk]]
[[Category: Tong L]]
[[Category: Cell cycle]]
[[Category: Cyclin dependent kinase]]
[[Category: Cyclin dependent kinase inhibitory protein]]
[[Category: Ink4]]
[[Category: Mts1]]
[[Category: Multiple tumor suppressor]]

Latest revision as of 09:36, 7 February 2024

MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEXMECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX

Structural highlights

1bi7 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.4Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CDK6_HUMAN Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans.[1] [2] [3] [4] [5] [6] [7] [8] [9]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Meyerson M, Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077-86. PMID:8114739
  2. ↑ Matushansky I, Radparvar F, Skoultchi AI. CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells. Oncogene. 2003 Jul 3;22(27):4143-9. PMID:12833137 doi:10.1038/sj.onc.1206484
  3. ↑ Lucas JJ, Domenico J, Gelfand EW. Cyclin-dependent kinase 6 inhibits proliferation of human mammary epithelial cells. Mol Cancer Res. 2004 Feb;2(2):105-14. PMID:14985467
  4. ↑ Ogasawara T, Kawaguchi H, Jinno S, Hoshi K, Itaka K, Takato T, Nakamura K, Okayama H. Bone morphogenetic protein 2-induced osteoblast differentiation requires Smad-mediated down-regulation of Cdk6. Mol Cell Biol. 2004 Aug;24(15):6560-8. PMID:15254224 doi:10.1128/MCB.24.15.6560-6568.2004
  5. ↑ Takaki T, Fukasawa K, Suzuki-Takahashi I, Semba K, Kitagawa M, Taya Y, Hirai H. Preferences for phosphorylation sites in the retinoblastoma protein of D-type cyclin-dependent kinases, Cdk4 and Cdk6, in vitro. J Biochem. 2005 Mar;137(3):381-6. PMID:15809340 doi:10.1093/jb/mvi050
  6. ↑ Fujimoto T, Anderson K, Jacobsen SE, Nishikawa SI, Nerlov C. Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007 May 2;26(9):2361-70. Epub 2007 Apr 12. PMID:17431401 doi:10.1038/sj.emboj.7601675
  7. ↑ Ruas M, Gregory F, Jones R, Poolman R, Starborg M, Rowe J, Brookes S, Peters G. CDK4 and CDK6 delay senescence by kinase-dependent and p16INK4a-independent mechanisms. Mol Cell Biol. 2007 Jun;27(12):4273-82. Epub 2007 Apr 9. PMID:17420273 doi:10.1128/MCB.02286-06
  8. ↑ Fiaschi-Taesch NM, Salim F, Kleinberger J, Troxell R, Cozar-Castellano I, Selk K, Cherok E, Takane KK, Scott DK, Stewart AF. Induction of human beta-cell proliferation and engraftment using a single G1/S regulatory molecule, cdk6. Diabetes. 2010 Aug;59(8):1926-36. doi: 10.2337/db09-1776. PMID:20668294 doi:10.2337/db09-1776
  9. ↑ Sarek G, Jarviluoma A, Moore HM, Tojkander S, Vartia S, Biberfeld P, Laiho M, Ojala PM. Nucleophosmin phosphorylation by v-cyclin-CDK6 controls KSHV latency. PLoS Pathog. 2010 Mar 19;6(3):e1000818. doi: 10.1371/journal.ppat.1000818. PMID:20333249 doi:10.1371/journal.ppat.1000818

1bi7, resolution 3.40Å

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