Regulation of T-Type Cyclin/CDK9 Complexes in Breast Cancer Cells

摘要

Positive transcription elongation b (P-TEFb) is a general transcription elongation factor and is composed of a catalytic subunit, CDK9, and a regulatory subunit, a T-type cyclin. The complex phosphorylates the C- terminal domain of RNA polymerase II as well as negative elongation factors to allow for the transcriptional elongation of paused transcripts. We have investigated the regulation and role of cyclin T1 in breast cancer cells. While cyclin T1 expression is regulated by multiple signaling pathways in T cells, it is constitutively expressed in breast cancer cells. Also, cyclin T1 associated kinase activity is not regulated in PMA treated MCF-7 and T47D cells. Flavopiridol (FVP), a drug being evaluated in clinical trials as an anti-cancer agent, and a potent inhibitor of HIV transcription, is believed to act, at least in part, by inhibiting CDK9. We have compared the effects of FVP with those effects induced by direct inhibition of CDK9 by a dominant negative (dnCDK9) in breast cancer cells and found that both treatments result in p53- independent apoptosis of breast cancer cells.