P190B RhoGAP regulates chromosome segregation in cancer cells

Melissa Hwang, Sirisha Peddibhotla, Peter McHenry, Peggy Chang, Zachary Yochum, Ko Un Park, James Cooper Sears, Tracy Vargo-Gogola

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)475-489
Number of pages15
JournalCancers
Volume4
Issue number2
DOIs
StatePublished - Jun 1 2012

Keywords

  • Aneuploidy
  • Breast cancer
  • Centrosome
  • Chromosome segregation
  • Mitosis
  • P190B RhoGAP
  • Rho GTPases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Hwang, M., Peddibhotla, S., McHenry, P., Chang, P., Yochum, Z., Park, K. U., Sears, J. C., & Vargo-Gogola, T. (2012). P190B RhoGAP regulates chromosome segregation in cancer cells. Cancers, 4(2), 475-489. https://doi.org/10.3390/cancers4020475