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

doi:10.4161/cc.8.8.8205

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

Academic Institute

Research output: Contribution to journal › Article › peer-review

40 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 language	English (US)
Pages (from-to)	1206-1216
Number of pages	11
Journal	Cell Cycle
Volume	8
Issue number	8
DOIs	https://doi.org/10.4161/cc.8.8.8205
State	Published - 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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10.4161/cc.8.8.8205

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@article{8c510c4c7375473f918f68bb4bbf664d,

title = "CDK5RAP2 is required for spindle checkpoint function",

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.",

keywords = "BUBR1, CDK5RAP2, Doxorubicin, Drug resistance, MAD2, Paclitaxel, Primary microcephaly, Spindle checkpoint",

author = "Xiaoying Zhang and Dongyun Liu and Shuang Lv and Haibo Wang and Xueyan Zhong and Bo Liu and Bo Wang and Ji Liao and Jing Li and Pfeifer, {Gerd P.} and Xingzhi Xu",

note = "Funding Information: We thank Eric W. McIntush from the Bethyl Laboratories for CDK5RAP2 antibodies. We thank other members of the Xu{\textquoteright}s laboratory for help. This work was supported by the startup fund from CNU, NSFC funds (30570371, 90608014 and 30711120570), the Program for New Century Excellent Talents in University (NCET-06-0187), Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ200810028014), and Funding Project for Academic Human Resources Development in Funding Information: Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (PHR(IHLB)) to X.X., and a National Institutes of Health grant (R01CA88873) to G.P.P. J.L is supported by NSFC fund 30700420 & Beijing Nova Program 2007B062.",

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month = apr,

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doi = "10.4161/cc.8.8.8205",

language = "English (US)",

volume = "8",

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TY - JOUR

T1 - CDK5RAP2 is required for spindle checkpoint function

AU - Zhang, Xiaoying

AU - Liu, Dongyun

AU - Lv, Shuang

AU - Wang, Haibo

AU - Zhong, Xueyan

AU - Liu, Bo

AU - Wang, Bo

AU - Liao, Ji

AU - Li, Jing

AU - Pfeifer, Gerd P.

AU - Xu, Xingzhi

N1 - Funding Information: We thank Eric W. McIntush from the Bethyl Laboratories for CDK5RAP2 antibodies. We thank other members of the Xu’s laboratory for help. This work was supported by the startup fund from CNU, NSFC funds (30570371, 90608014 and 30711120570), the Program for New Century Excellent Talents in University (NCET-06-0187), Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ200810028014), and Funding Project for Academic Human Resources Development in Funding Information: Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (PHR(IHLB)) to X.X., and a National Institutes of Health grant (R01CA88873) to G.P.P. J.L is supported by NSFC fund 30700420 & Beijing Nova Program 2007B062.

PY - 2009/4/15

Y1 - 2009/4/15

N2 - 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.

AB - 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.

KW - BUBR1

KW - CDK5RAP2

KW - Doxorubicin

KW - Drug resistance

KW - MAD2

KW - Paclitaxel

KW - Primary microcephaly

KW - Spindle checkpoint

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JO - Cell Cycle

JF - Cell Cycle

IS - 8

ER -

CDK5RAP2 is required for spindle checkpoint function

Abstract

Keywords

ASJC Scopus subject areas

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