CDK9
Description
The CDK9 (cyclin dependent kinase 9) is a protein-coding gene located on chromosome 9.
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. CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle.
== 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.
== Interactions == CDK9 has been shown to interact with:
== References ==
== Further reading ==
== See also == Enitociclib
== External links == Cyclin-Dependent+Kinase+9 at the U.S. National Library of Medicine Medical Subject Headings (MeSH) Drosophila Cyclin dependent kinase 9 - The Interactive Fly CDK9 human gene location in the UCSC Genome Browser.
CDK9 is a protein kinase that plays a crucial role in regulating transcription. It is a member of the cyclin-dependent kinase family and forms a complex with cyclin-T, known as positive transcription elongation factor b (P-TEFb). P-TEFb facilitates the transition from abortive to productive elongation during transcription by phosphorylating the C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAP II), which includes POLR2A, SUPT5H, and RDBP. CDK9 also phosphorylates various proteins involved in transcription regulation, including EP300, MYOD1, RPB1/POLR2A, AR, and the negative elongation factors DSIF and NELFE. This phosphorylation activity contributes to the regulation of cytokine inducible transcription networks, RNA synthesis, cell growth, differentiation, and viral pathogenesis. Furthermore, CDK9 is involved in cotranscriptional histone modifications, mRNA processing, and mRNA export. It modulates a complex network of chromatin modifications, including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3), and H3K36me3, and integrates phosphorylation during transcription with these chromatin modifications to control co-transcriptional histone mRNA processing. CDK9/cyclin-K complex also exhibits kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. This complex is essential for maintaining genome integrity by promoting cell cycle recovery from replication arrest, limiting single-stranded DNA amount in response to replication stress, and reducing the breakdown of stalled replication forks. Additionally, CDK9 isoform 2 may play a role in DNA repair through interaction with KU70/XRCC6. CDK9 promotes cardiac myocyte enlargement, and the phosphorylation of MYOD1 enhances its transcriptional activity, leading to muscle differentiation. CDK9 also catalyzes the phosphorylation of KAT5, promoting its recruitment to chromatin and histone acetyltransferase activity. CDK9 is a component of the super elongation complex (SEC) and associates with CCNT1/cyclin-T1, CCNT2/cyclin-T2, or CCNK/cyclin-K to form active P-TEFb. P-TEFb forms a complex with AFF4/AF5Q31 and is part of the SEC. It also interacts with UBR5 and forms a transcription regulatory complex that can stimulate target gene transcription. CDK9 is a component of the 7SK snRNP inactive complex, which can also interact with NCOR1 and HDAC3 to regulate CDK9 acetylation. The release of P-TEFb from this complex requires PP2B and PPP1CA, and the released P-TEFb remains inactive until further phosphorylation occurs. CDK9 interacts with BRD4 to target chromatin binding and with JMJD6. It also interacts with activated nuclear STAT3 and RELA/p65, and binds to AR and MYOD1. CDK9 forms a complex with CCNT1/cyclin-T1, EP300, and GATA4 that stimulates hypertrophy in cardiomyocytes. It also interacts with HSF1 and TBX21. CDK9 isoform 3 binds to KU70/XRCC6, and interacts with WDR43 and ZMYND8. During microbial infection, CDK9 interacts with the acidic/proline-rich region of HIV-1 and HIV-2 Tat via the T-loop region, enabling HIV to hijack host transcription machinery. It also interacts with human herpes virus 1 (HHV-1) protein ICP22, which blocks the recruitment of P-TEFb to the viral promoter.
CDK9 is also known as C-2k, CDC2L4, CTK1, PITALRE, TAK.
