CDK5RAP2 is required for spindle checkpoint function

Xiaoying Zhang, Dongyun Liu, Shuang Lv, Haibo Wang, Xueyan Zhong, Bo Liu, Bo Wang, Ji Liao, Jing Li, Gerd P. Pfeifer, Xingzhi Xu

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The combination of paclitaxel and doxorubicin is among the most successful chemotherapy regimens in cancer treatment. CDK5RAP2, when mutated, causes primary microcephaly. We show here that inhibition of CDK5RAP2 expression causes chromosome mis-segregation, fails to maintain the spindle checkpoint, and is associated with reduced expression of the spindle checkpoint proteins BUBR1 and MAD2 and an increase in chromatin-associated CDC20. CDK5RAP2 resides on the BUBR1 and MAD2 promoters and regulates their transcription. Furthermore, CDK5RAP2-knockdown cells have increased resistance to paclitaxel and doxorubicin, and this resistance is partially rescued upon restoration of CDK5RAP2 expression. Cancer cells cultured in the presence of paclitaxel or doxorubicin exhibit dramatically decreased CDK5RAP2 levels. These results suggest that CDK5RAP2 is required for spindle checkpoint function and is a common target in paclitaxel and doxorubicin resistance.

Original languageEnglish (US)
Pages (from-to)1206-1216
Number of pages11
JournalCell Cycle
Volume8
Issue number8
DOIs
StatePublished - Apr 15 2009

Keywords

  • BUBR1
  • CDK5RAP2
  • Doxorubicin
  • Drug resistance
  • MAD2
  • Paclitaxel
  • Primary microcephaly
  • Spindle checkpoint

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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