CDK5RAP2 is required for spindle checkpoint function.
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.
Zhang
Xiaoying
X
Laboratory of Cancer Biology, Capital Normal University College of Life Science, Beijing, China.
Liu
Dongyun
D
Lv
Shuang
S
Wang
Haibo
H
Zhong
Xueyan
X
Liu
Bo
B
Wang
Bo
B
Liao
Ji
J
Li
Jing
J
Pfeifer
Gerd P
GP
Xu
Xingzhi
X
D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D020090:Chromosome Segregation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064246:Mad2 Proteins; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
C405929:CDK5RAP2 protein, human; D002135:Calcium-Binding Proteins; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C577488:CDC20 protein, human; D004317:Doxorubicin; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel