Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P23193 (transcription elongation factor)
 739 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinases (CDKs) are potential cancer therapeutic targets because of their critical role in promoting cell growth. Dinaciclib is a novel CDK inhibitor currently under clinical evaluation for the treatment of advanced malignancies. In this study, we demonstrated the anti-tumor activity of dinaciclib in triple negative breast cancer (TNBC) patient derived xenograft (PDX) and cell lines in vitro and in vivo. Treatment with dinaciclib induced cell cycle arrest at G2/M phase and marked apoptosis. These changes were accompanied by reduced phosphorylation of CDK1 and retinoblastoma (Rb) protein and decreased protein levels of cyclin B1, cMYC and survivin. We further demonstrated that siRNA knockdown of CDK9, the kinase subunit of positive transcription elongation factor b (P-TEFb), instead of CDK1 or CDK2, reduced the levels of cyclin B1 and MYC in TNBC cell lines. These data support the importance of CDK9, in addition to CDK1, in mediating the growth inhibitory effect of dinaciclib in TNBC. Further investigation of CDK9 as a therapeutic target in TNBC is needed.
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PMID:Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer. 2748 54

The more than 500 protein kinases comprising the human kinome catalyze hundreds of thousands of phosphorylation events to regulate a diversity of cellular functions; however, the extended substrate specificity is still unknown for many of these kinases. We report here a method for quantitatively describing kinase substrate specificity using an unbiased peptide library-based approach with direct measurement of phosphorylation by tandem liquid chromatography-tandem mass spectrometry (LC-MS/MS) peptide sequencing (multiplex substrate profiling by mass spectrometry, MSP-MS). This method can be deployed with as low as 10 nM enzyme to determine activity against S/T/Y-containing peptides; additionally, label-free quantitation is used to ascertain catalytic efficiency values for individual peptide substrates in the multiplex assay. Using this approach we developed quantitative motifs for a selection of kinases from each branch of the kinome, with and without known substrates, highlighting the applicability of the method. The sensitivity of this approach is evidenced by its ability to detect phosphorylation events from nanogram quantities of immunoprecipitated material, which allows for wider applicability of this method. To increase the information content of the quantitative kinase motifs, a sublibrary approach was used to expand the testable sequence space within a peptide library of approximately 100 members for CDK1, CDK7, and CDK9. Kinetic analysis of the HIV-1 Tat (transactivator of transcription)-positive transcription elongation factor b (P-TEFb) interaction allowed for localization of the P-TEFb phosphorylation site as well as characterization of the stimulatory effect of Tat on P-TEFb catalytic efficiency.
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PMID:Multiplex Substrate Profiling by Mass Spectrometry for Kinases as a Method for Revealing Quantitative Substrate Motifs. 2832 50