CDK9

GeneName

CDK9

Summary

CDK9, also known as TAK or cyclin dependent kinase 9, is a 43 kDa serine/threonine kinase that plays a pivotal role in the regulation of transcription elongation by RNA polymerase II. It is part of the P-TEFb complex, which is essential for the positive regulation of transcription elongation and is involved in various cellular processes such as cell cycle regulation, DNA repair, and response to cytokine stimuli. CDK9 is expressed in the nucleus and cytoplasm, and is associated with several cellular components including the transcription elongation factor complex and cytoplasmic ribonucleoprotein granules. Its function is mediated through interactions with cyclins and other transcription factors, facilitating the phosphorylation of the RNA polymerase II C-terminal domain, thereby enhancing transcriptional activity.

Importance

CDK9 is relevant to: - The regulation of gene expression through its role in transcription elongation, impacting various biological processes including cell proliferation and differentiation. - Viral transcription regulation, as it positively influences the transcription of viral genes, making it a target for antiviral strategies. - Cancer research, due to its involvement in cell cycle regulation and potential contributions to oncogenesis, highlighting its role in tumour biology. - Therapeutic targeting, as inhibitors of CDK9 are being explored for their potential in treating cancers and other diseases associated with dysregulated transcription.

Top Products

For researchers investigating CDK9, we highly recommend the top-selling recombinant antibody, Anti-Cdk9 antibody [EPR3119Y] (ab76320). This antibody has been validated for use in a variety of applications, including Western blotting (WB), immunohistochemistry (IHC), immunoprecipitation (IP), immunocytochemistry (ICC), and flow cytometry (FC). With 21 citations, it has garnered attention in the research community, showcasing its reliability and effectiveness for CDK9 detection. This product is an excellent choice for those seeking the consistency and performance that recombinant antibodies offer.

Abcam Product Citation Summary

The data indicates that CDK9 is primarily studied in human cell lines, particularly HEK-293T and various liver cell lines, using Western blotting as the main application. The research contexts include investigations into P-TEFb interacting partners, regulation of CDK9 expression, and the effects of specific microRNAs and gene expression regulation. Additionally, CDK9's role in TRAIL signaling pathway modulation is also explored.

Abcam Product Citation Table

Function

Protein kinase involved in the regulation of transcription (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094, PubMed:29335245). Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:16427012, PubMed:20930849, PubMed:28426094, PubMed:30134174). This complex is inactive when in the 7SK snRNP complex form (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELFE (PubMed:10912001, PubMed:11112772, PubMed:12037670, PubMed:16427012, PubMed:20081228, PubMed:20980437, PubMed:21127351, PubMed:9857195). Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling) (PubMed:17956865, PubMed:18362169). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis (PubMed:10393184, PubMed:11112772). P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export (PubMed:15564463, PubMed:19575011, PubMed:19844166, PubMed:28539972). Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing (PubMed:15564463, PubMed:19575011, PubMed:19844166). Also catalyzes phosphorylation of histone H1.4 (H1-4) at Ser-187' (H1.4S187Ph), a modification associated with transcription activation (PubMed:28539972). The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro (PubMed:21127351). Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage (PubMed:20493174). In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6 (PubMed:20493174). Promotes cardiac myocyte enlargement (PubMed:20081228). RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription (PubMed:21127351). AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect (PubMed:10912001, PubMed:11112772, PubMed:9857195). The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation (PubMed:12037670). Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity (PubMed:29335245).

Involvement in disease

Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy and confers predisposition to heart failure.

Post-translational modifications

Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354 and Ser-357 triggers kinase activity by promoting cyclin and substrate binding (e.g. HIV TAT) upon conformational changes. Thr-186 phosphorylation requires the calcium Ca(2+) signaling pathway, including CaMK1D and calmodulin. This inhibition is relieved by Thr-29 dephosphorylation. However, phosphorylation at Thr-29 is inhibitory within the HIV transcription initiation complex. Phosphorylation at Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously (PubMed:18566585).

Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9 activity and may lead to CDK9 proteasomal degradation (PubMed:18483222, PubMed:18829461). However, PPP1CA-mediated Thr-186 dephosphorylation is required to release P-TEFb from its inactive P-TEFb/7SK snRNP complex (PubMed:18483222, PubMed:18829461). Dephosphorylated at Ser-347 by the PNUTS-PP1 complex during RNA polymerase II transcription pause-release (PubMed:39603239). Dephosphorylation of C-terminus Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9 activity, contributing to the activation of HIV-1 transcription.

N6-acetylation of Lys-44 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity (PubMed:17452463, PubMed:18250157). The acetylated form associates with PML bodies in the nuclear matrix and with the transcriptionally silent HIV-1 genome; deacetylated upon transcription stimulation (PubMed:17452463, PubMed:18250157). Deacetylated by SIRT7, promoting the kinase activity and subsequent 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (PubMed:28426094).

Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD.

Sequence Similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Tissue Specificity

Ubiquitous.

Cellular localization

• Nucleus
• Cytoplasm
• Nucleus
• PML body
• Accumulates on chromatin in response to replication stress. Complexed with CCNT1 in nuclear speckles, but uncomplexed form in the cytoplasm. The translocation from nucleus to cytoplasm is XPO1/CRM1-dependent. Associates with PML body when acetylated.

Alternative names

CDC2L4, TAK, CDK9, Cyclin-dependent kinase 9, C-2K, Cell division cycle 2-like protein kinase 4, Cell division protein kinase 9, Serine/threonine-protein kinase PITALRE, Tat-associated kinase complex catalytic subunit

Database links

swissprot:P50750 entrezGene:905 omim:603862 swissprot:O60583 entrezGene:1025 omim:603251