Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology

Wang, Shudong; Fischer, Peter M.

doi:10.1016/j.tips.2008.03.003

Cited by 202 publications

(208 citation statements)

References 115 publications

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“…CDK9 is a member of the CDK family of serine-threonine kinases that forms the catalytic core of P-TEFb and, in the presence of cyclin T, stimulates transcription elongation by RNA polymerase II (RNA Pol II) (Peterlin and Price 2006). Many small molecule drugs initially designed to target other CDKs also target CDK9, and it is now recognized that CDK9 inhibition contributes to their anti-proliferative effects (Wang and Fischer 2008). However, molecular determi- Table 2).…”

Section: Pharmacological Inhibition Of Cdk9 In Hcc Cell Linesmentioning

confidence: 99%

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

et al. 2014

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One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.

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Section: Pharmacological Inhibition Of Cdk9 In Hcc Cell Linesmentioning

confidence: 99%

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

et al. 2014

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“…Coupled with CDK9, Ccnt2 forms a complex known as 'positive transcription elongation factor b' (P-TEFb), which is generally considered to function in a cell cycle-independent manner [26] and is involved in muscle differentiation [19,27]. Eight mouse cell lines were collected for the detection of Ccnt2 and miR-15a.…”

Section: Ccnt2 Is a Direct Target Of Mir-15amentioning

confidence: 99%

Cyclin T2: A novel miR‐15a target gene involved in early spermatogenesis

Teng

Wang

et al. 2011

FEBS Letters

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Edited by Tamas DalmayKeywords: miR-15a Cyclin T2 Cell differentiation Spermatogenesis MicroRNA microarray a b s t r a c t MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression that play important roles in various biological processes. Spermatogenesis is a highly regulated process in which diploid spermatogonia eventually differentiate into haploid spermatozoa. In this study, we identified four differentially expressed miRNAs between two premeiotic male germ cells, made predictions about their putative targets, and confirmed cyclin T2 (Ccnt2) as a direct target of miR-15a. We also report that miR-15a inhibited muscle differentiation at least in part by targeting Ccnt2, which represents a novel interaction. Subsequently, miR-15a and Ccnt2 were profiled in developing mice testes to observe their inverse correlations in the postnatal 3-week period to understand their roles in spermatogenesis.

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“…The p-TEFb complex is thought to be comprised of CDK9 as the catalytic subunit and one of three cyclins T1, T2 or K, as the regulatory subunit. 31,42 Of note, we detected two additional proteins with inhibition profiles closely matching those of CDK9 and cyclin T1, the Table S1) and normal B cells. Kinases and associated proteins were isolated from CLL cell samples and from a pool of B cells from six healthy donors, and were subjected to quantitative LC-MS/MS profiling.…”

Section: Discussionmentioning

confidence: 71%

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

Kruse¹,

Pallasch

Bantscheff³

et al. 2010

Leukemia

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The pharmacological induction of apoptosis in neoplastic B cells presents a promising therapeutic avenue for the treatment of chronic lymphocytic leukemia (CLL). We profiled a panel of clinical multi-kinase inhibitors for their ability to induce apoptosis in primary CLL cells. Whereas inhibitors targeting a large number of receptor and intracellular tyrosine kinases including c-KIT, FLT3, BTK and SYK were comparatively inactive, the CDK inhibitors BMS-387032 and flavopiridol showed marked efficacy similar to staurosporine. Using the kinobeads proteomics method, kinase expression profiles and binding profiles of the inhibitors to target protein complexes were quantitatively monitored in CLL cells. The targets most potently affected were CDK9, cyclin T1, AFF3/4 and MLLT1, which may represent four subunits of a deregulated positive transcriptional elongation factor (p-TEFb) complex. Albeit with lower potency, both drugs also bound the basal transcription factor BTF2/TFIIH containing CDK7. Staurosporine and geldanamycin do not affect these targets and thus seem to exhibit a different mechanism of action. The data support a critical role of p-TEFb inhibitors in CLL that supports their future clinical development.

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Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology

Cited by 202 publications

References 115 publications

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

Cyclin T2: A novel miR‐15a target gene involved in early spermatogenesis

Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells

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