HEXIM1 controls P-TEFb processing and regulates drug sensitivity in triple-negative breast cancer.

Molecular Biology of the Cell
Hengyi ShaoKunxin Luo

Abstract

The positive transcription elongation factor b (P-TEFb), composed of CDK9 and cyclin T, stimulates transcriptional elongation by RNA polymerase (Pol) II and regulates cell growth and differentiation. Recently, we demonstrated that P-TEFb also controls the expression of EMT regulators to promote breast cancer progression. In the nucleus, more than half of P-TEFb are sequestered in the inactive-state 7SK snRNP complex. Here, we show that the assembly of the 7SK snRNP is preceded by an intermediate complex between HEXIM1 and P-TEFb that allows transfer of the kinase active P-TEFb from Hsp90 to 7SK snRNP for its suppression. Down-regulation of HEXIM1 locks P-TEFb in the Hsp90 complex, keeping it in the active state to enhance breast cancer progression, but also rendering the cells highly sensitive to Hsp90 inhibition. Because HEXIM1 is often down-regulated in human triple-negative breast cancer (TNBC), these cells are particularly sensitive to Hsp90 inhibition. Our study provides a mechanistic explanation for the increased sensitivity of TNBC to Hsp90 inhibition.

References

Feb 13, 2003·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Rika OuchidaHirotoshi Tanaka
Jun 18, 2004·The EMBO Journal·Annemieke A MichelsOlivier Bensaude
Sep 22, 2005·Nature Reviews. Cancer·Luke Whitesell, Susan L Lindquist
Nov 1, 2006·Molecular and Cellular Biology·Qingwei ZhuKunxin Luo
Dec 18, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David B SolitPaul B Chapman
May 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Eloisi Caldas-LopesGabriela Chiosis
Dec 4, 2009·PLoS Biology·Dorothee MuellerRobert K Slany
Apr 23, 2010·International Journal of Urology : Official Journal of the Japanese Urological Association·Yasutomo SuzukiTaiji Nishimura
Mar 23, 2011·Oncogene·W KetchartM M Montano
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Nov 22, 2011·Cell Host & Microbe·Melanie OttQiang Zhou
Feb 22, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kim H T ParaisoKeiran S M Smalley
Mar 13, 2012·Annual Review of Biochemistry·Qiang ZhouDavid H Price
Oct 2, 2012·Nature Chemical Biology·Georg E WinterGiulio Superti-Furga
Dec 25, 2013·Proceedings of the National Academy of Sciences of the United States of America·Huasong LuQiang Zhou
Nov 5, 2016·Cancer Research·Guillaume AndrieuGerald V Denis
Sep 8, 2017·Nature Communications·Rina M MbofungPatrick Hwu
Jul 18, 2018·Proceedings of the National Academy of Sciences of the United States of America·Chunyan RenMing-Ming Zhou

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
xenograft
immunoprecipitation
affinity purification
electrophoresis
coimmunoprecipitation
PCR
flow cytometry

Software Mentioned

Graphpad Prism
ImageJ

Related Concepts

Related Feeds

Breast Cancer Triple-N

Breast cancer cells have receptors for estrogen, progesterone, HER2 receptors (also called ERBB2). Triple-negative breast cancers do not have any of these receptors. Here are the latest discoveries pertaining to triple-negative breast cancers.