Brd4-dependent CDK9 expression induction upon sustained pharmacological inhibition of P-TEFb kinase activity
1Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Abstract:
CDK9 is the kinase subunit of P-TEFb (positive transcription elongation factor b), which is crucial for effective transcriptional elongation. The activity of P-TEFb is well maintained, mainly through dynamic association with several larger protein complexes. Here, we show that CDK9 expression is induced upon inhibition of P-TEFb activity, a process dependent on Brd4 as later revealed. Brd4 inhibition synergizes with CDK9 inhibitor to suppress P-TEFb activity and tumor cell growth. Our study suggests that combined inhibition of Brd4 and CDK9 can be evaluated as a potential therapeutic strategy.
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