P190B RhoGAP Regulates Chromosome Segregation in Cancer Cells

Cancers

Melissa Hwang³  Sirisha Peddibhotla²  Peter McHenry¹  Peggy Chang³  Zachary Yochum³  Ko Un Park³  James Cooper Sears³ 

[1] Department of Biology, Southwestern Adventist University, 100 W. Hillcrest, Keene, TX 76059, USA; E-Mail:;Department of Molecular and Human Genetics, Baylor College of Medicine, John P. McGovern Campus, NABS-0250, Houston, TX 77030, USA; E-Mail:;Department of Biochemistry and Molecular Biology and the Indiana University Simon Cancer Center, Indiana University School of Medicine, 1234 Notre Dame Avenue, South Bend, IN 46617, USA; E-Mails:

关键词: p190B RhoGAP;    mitosis;    chromosome segregation;    centrosome;    aneuploidy;    Rho GTPases;    breast cancer;   

DOI  :  10.3390/cancers4020475

来源: mdpi

【 摘 要 】

Rho GTPases are overexpressed and hyperactivated in many cancers, including breast cancer. Rho proteins, as well as their regulators and effectors, have been implicated in mitosis, and their altered expression promotes mitotic defects and aneuploidy. Previously, we demonstrated that p190B Rho GTPase activating protein (RhoGAP) deficiency inhibits ErbB2-induced mammary tumor formation in mice. Here we describe a novel role for p190B as a regulator of mitosis. We found that p190B localized to centrosomes during interphase and mitosis, and that it is differentially phosphorylated during mitosis. Knockdown of p190B expression in MCF-7 and Hela cells increased the incidence of aberrant microtubule-kinetochore attachments at metaphase, lagging chromosomes at anaphase, and micronucleation, all of which are indicative of aneuploidy. Cell cycle analysis of p190B deficient MCF-7 cells revealed a significant increase in apoptotic cells with a concomitant decrease in cells in G1 and S phase, suggesting that p190B deficient cells die at the G1 to S transition. Chemical inhibition of the Rac GTPase during mitosis reduced the incidence of lagging chromosomes in p190B knockdown cells to levels detected in control cells, suggesting that aberrant Rac activity in the absence of p190B promotes chromosome segregation defects. Taken together, these data suggest that p190B regulates chromosome segregation and apoptosis in cancer cells. We propose that disruption of mitosis may be one mechanism by which p190B deficiency inhibits tumorigenesis.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.