View source for Cyclin-dependent kinase 9

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}
'''Cyclin-dependent kinase 9''' or '''CDK9''' is a [[cyclin-dependent kinase]] associated with [[P-TEFb]].

== Function ==

The protein encoded by this gene is a member of the [[cyclin-dependent kinase]] (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the [[C-terminal]] domain of the largest subunit of [[RNA polymerase II]]. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS.<ref>{{cite web | title = Entrez Gene: CDK9 cyclin-dependent kinase 9 (CDC2-related kinase)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1025}}</ref>

CDK9 is also known to associate with other proteins such as [[TRAF2]], and be involved in differentiation of skeletal muscle.<ref name="pmid9827693">{{cite journal | vauthors = MacLachlan TK, Sang N, De Luca A, Puri PL, Levrero M, Giordano A | title = Binding of CDK9 to TRAF2 | journal = J. Cell. Biochem. | volume = 71 | issue = 4 | pages = 467–78 | year = 1998 | pmid = 9827693 | doi = 10.1002/(SICI)1097-4644(19981215)71:4<467::AID-JCB2>3.0.CO;2-G | s2cid = 25858837 }}</ref>

==Inhibitors==
Based on molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms. Analysis of MD simulations and MM-PBSA studies, revealed the binding energy profiles of all the selected complexes. Selected ligands performed better than the experimental drug candidate (Roscovitine). Ligands-5 and 16 show specificity for CDK9. These ligands are expected to possess lower risk of side effects due to their natural origin. <ref name="pmid3176087">{{cite journal | vauthors = Singh R, Bhardwaj VK, Das P, Purohit R | title = Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective | journal = Journal of Biomolecular Structure and Dynamics | volume = 38 | issue = 17 |date= November 2019 | pages = 5126–5135 | pmid = 3176087 | doi = 10.1080/07391102.2019.1696709 | s2cid = 208276454 }}</ref>

==Interactions==
CDK9 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[Androgen receptor]],<ref name = pmid11266437>{{cite journal | date = March 2001 | vauthors = Lee DK, Duan HO, Chang C | title = Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation | journal = J. Biol. Chem. | volume = 276 | issue = 13 | pages = 9978–84 | pmid = 11266437 | doi = 10.1074/jbc.M002285200| doi-access = free }}</ref> 
* [[CDC34]]<ref name = pmid11689688/> and 
* [[Cyclin K|CCNK]],<ref name = pmid10574912>{{cite journal | date = December 1999 | vauthors = Fu TJ, Peng J, Lee G, Price DH, Flores O | title = Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription | journal = J. Biol. Chem. | volume = 274 | issue = 49 | pages = 34527–30 | pmid = 10574912 | doi = 10.1074/jbc.274.49.34527| doi-access = free }}</ref> 
* [[Cyclin T1|CCNT1]],<ref name = pmid10574912/><ref name = pmid9499409/><ref name = pmid15107825>{{cite journal | date = July 2004 | vauthors = Cabart P, Chew HK, Murphy S | title = BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II | journal = Oncogene | volume = 23 | issue = 31 | pages = 5316–29 | pmid = 15107825 | doi = 10.1038/sj.onc.1207684| doi-access = free }}</ref><ref name = pmid12944466>{{cite journal | date = September 2003 | vauthors = Young TM, Wang Q, Pe'ery T, Mathews MB | title = The human I-mfa domain-containing protein, HIC, interacts with cyclin T1 and modulates P-TEFb-dependent transcription | journal = Mol. Cell. Biol. | volume = 23 | issue = 18 | pages = 6373–84 | pmid = 12944466 | pmc = 193714 | doi = 10.1128/MCB.23.18.6373-6384.2003}}</ref><ref name = pmid12832472>{{cite journal | date = July 2003 | vauthors = Michels AA, Nguyen VT, Fraldi A, Labas V, Edwards M, Bonnet F, Lania L, Bensaude O | title = MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner | journal = Mol. Cell. Biol. | volume = 23 | issue = 14 | pages = 4859–69 | pmid = 12832472 | pmc = 162212 | doi = 10.1128/MCB.23.14.4859-4869.2003}}</ref><ref name = pmid12588988>{{cite journal | date = March 2003 | vauthors = Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T | title = The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription | journal = Mol. Cell. Biol. | volume = 23 | issue = 5 | pages = 1688–702 | pmid = 12588988 | pmc = 151712 | doi = 10.1128/MCB.23.5.1688-1702.2003}}</ref><ref name = pmid11689688>{{cite journal | date = December 2001 | vauthors = Kiernan RE, Emiliani S, Nakayama K, Castro A, Labbé JC, Lorca T, Nakayama Ki K, Benkirane M | title = Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome | journal = Mol. Cell. Biol. | volume = 21 | issue = 23 | pages = 7956–70 | pmid = 11689688 | pmc = 99964 | doi = 10.1128/MCB.21.23.7956-7970.2001}}</ref><ref name = pmid10656684>{{cite journal | date = January 2000 | vauthors = De Falco G, Bagella L, Claudio PP, De Luca A, Fu Y, Calabretta B, Sala A, Giordano A | title = Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation | journal = Oncogene | volume = 19 | issue = 3 | pages = 373–9 | pmid = 10656684 | doi = 10.1038/sj.onc.1203305| doi-access = free | hdl = 11380/15896 | hdl-access = free }}</ref><ref name = pmid10958691>{{cite journal | date = September 2000 | vauthors = Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE, Jones KA | title = CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA | journal = Mol. Cell. Biol. | volume = 20 | issue = 18 | pages = 6958–69 | pmid = 10958691 | pmc = 88771 | doi = 10.1128/MCB.20.18.6958-6969.2000}}</ref> 
* [[Cyclin T2|CCNT2]],<ref name = pmid9499409>{{cite journal | date = March 1998 | vauthors = Peng J, Zhu Y, Milton JT, Price DH | title = Identification of multiple cyclin subunits of human P-TEFb | journal = Genes Dev. | volume = 12 | issue = 5 | pages = 755–62 | pmid = 9499409 | pmc = 316581 | doi = 10.1101/gad.12.5.755}}</ref> 
* [[MYBL2]],<ref name = pmid10656684/> 
* [[RELA]],<ref name = pmid12173051>{{cite journal | date = August 2002 | vauthors = Amini S, Clavo A, Nadraga Y, Giordano A, Khalili K, Sawaya BE | title = Interplay between cdk9 and NF-kappaB factors determines the level of HIV-1 gene transcription in astrocytic cells | journal = Oncogene | volume = 21 | issue = 37 | pages = 5797–803 | pmid = 12173051 | doi = 10.1038/sj.onc.1205754| doi-access = free }}</ref> 
* [[Retinoblastoma protein|RB1]],<ref name = pmid12037672>{{cite journal | date = June 2002 | vauthors = Simone C, Bagella L, Bellan C, Giordano A | title = Physical interaction between pRb and cdk9/cyclinT2 complex | journal = Oncogene | volume = 21 | issue = 26 | pages = 4158–65 | pmid = 12037672 | doi = 10.1038/sj.onc.1205511| doi-access = free }}</ref> 
* [[SKP1A]].<ref name = pmid11689688/> 
* [[SUPT5H]],<ref name = pmid10958691/> and
* [[RNAP II]].<ref>{{cite journal | date = July 2002 | vauthors = Kim YK, Bourgeois CF, Isel C, Churcher MJ, Karn J | title = Phosphorylation of the RNA Polymerase II Carboxyl-Terminal Domain by CDK9 Is Directly Responsible for Human Immunodeficiency Virus Type 1 Tat-Activated Transcriptional Elongation | journal = Mol Cell Biol | volume = 22 | issue = 13 | pages = 4622–4637 | pmid = 12052871 | doi = 10.1128/MCB.22.13.4622-4637.2002 | pmc = 133925 | doi-access = free }}</ref>
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==References==
{{reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal  | author=Jeang KT |title=Tat, Tat-associated kinase, and transcription. |journal=J. Biomed. Sci. |volume=5 |issue= 1 |pages= 24–7 |year= 1998 |pmid= 9570510 |doi=10.1007/BF02253352  }}
*{{cite journal  | vauthors=Yankulov K, Bentley D |title=Transcriptional control: Tat cofactors and transcriptional elongation. |journal=Curr. Biol. |volume=8 |issue= 13 |pages= R447–9 |year= 1998 |pmid= 9651670 |doi=10.1016/S0960-9822(98)70289-1  |s2cid=15480646 |doi-access=free |bibcode=1998CBio....8.R447Y }}
*{{cite journal  | vauthors=Romano G, Kasten M, De Falco G |title=Regulatory functions of Cdk9 and of cyclin T1 in HIV tat transactivation pathway gene expression. |journal=J. Cell. Biochem. |volume=75 |issue= 3 |pages= 357–68 |year= 2000 |pmid= 10536359 |doi=10.1002/(SICI)1097-4644(19991201)75:3<357::AID-JCB1>3.0.CO;2-K  |s2cid=43685090 |display-authors=etal}}
*{{cite journal  | vauthors=Marcello A, Zoppé M, Giacca M |title=Multiple modes of transcriptional regulation by the HIV-1 Tat transactivator. |journal=IUBMB Life |volume=51 |issue= 3 |pages= 175–81 |year= 2002 |pmid= 11547919 |doi=10.1080/152165401753544241  |s2cid=10931640 |doi-access=free }}
*{{cite journal  | vauthors=Huigen MC, Kamp W, Nottet HS |title=Multiple effects of HIV-1 trans-activator protein on the pathogenesis of HIV-1 infection. |journal=Eur. J. Clin. Invest. |volume=34 |issue= 1 |pages= 57–66 |year= 2004 |pmid= 14984439 |doi=10.1111/j.1365-2362.2004.01282.x  |s2cid=29713968 }}
*{{cite journal  | vauthors=Rice AP, Herrmann CH |title=Regulation of TAK/P-TEFb in CD4+ T lymphocytes and macrophages. |journal=Curr. HIV Res. |volume=1 |issue= 4 |pages= 395–404 |year= 2004 |pmid= 15049426 |doi=10.2174/1570162033485159  }}
*{{cite journal  | vauthors=Minghetti L, Visentin S, Patrizio M |title=Multiple actions of the human immunodeficiency virus type-1 Tat protein on microglial cell functions. |journal=Neurochem. Res. |volume=29 |issue= 5 |pages= 965–78 |year= 2004 |pmid= 15139295 |doi=10.1023/B:NERE.0000021241.90133.89  |s2cid=25323034 |display-authors=etal}}
*{{cite journal  | vauthors=Liou LY, Herrmann CH, Rice AP |title=HIV-1 infection and regulation of Tat function in macrophages. |journal=Int. J. Biochem. Cell Biol. |volume=36 |issue= 9 |pages= 1767–75 |year= 2005 |pmid= 15183343 |doi= 10.1016/j.biocel.2004.02.018 }}
*{{cite journal  | vauthors=Pugliese A, Vidotto V, Beltramo T |title=A review of HIV-1 Tat protein biological effects. |journal=Cell Biochem. Funct. |volume=23 |issue= 4 |pages= 223–7 |year= 2005 |pmid= 15473004 |doi= 10.1002/cbf.1147 |s2cid=8408278 |display-authors=etal}}
*{{cite journal  | vauthors=Bannwarth S, Gatignol A |title=HIV-1 TAR RNA: the target of molecular interactions between the virus and its host. |journal=Curr. HIV Res. |volume=3 |issue= 1 |pages= 61–71 |year= 2005 |pmid= 15638724 |doi=10.2174/1570162052772924  }}
*{{cite journal  | vauthors=Gibellini D, Vitone F, Schiavone P, Re MC |title=HIV-1 tat protein and cell proliferation and survival: a brief review. |journal=New Microbiol. |volume=28 |issue= 2 |pages= 95–109 |year= 2005 |pmid= 16035254 }}
*{{cite journal  | author=Peruzzi F |title=The multiple functions of HIV-1 Tat: proliferation versus apoptosis. |journal=Front. Biosci. |volume=11 |pages= 708–17 |year= 2006 |pmid= 16146763 |doi=10.2741/1829  |doi-access=free }}
{{refend}}

== See also ==
* [[Enitociclib]] 

==External links==
* {{MeshName|Cyclin-Dependent+Kinase+9}}
* [http://www.sdbonline.org/fly/polycomb/cdk9-1.htm ''Drosophila'' ''Cyclin dependent kinase 9'' - The Interactive Fly]
* {{UCSC genome browser|CDK9}}
* {{UCSC gene details|CDK9}}

{{Cell cycle proteins}}
{{Serine/threonine-specific protein kinases}}
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{{DEFAULTSORT:Cyclin-dependent kinase 09}}
[[Category:Cell cycle]]
[[Category:Proteins]]
[[Category:EC 2.7.11]]


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