CUL7 is a novel antiapoptotic oncogene.
Using an expression cloning approach, we identify CUL7, a member of the cullin family, as a functional inhibitor of Myc-induced apoptosis. Deregulated expression of the Myc oncogene drives cellular proliferation yet also sensitizes cells to undergo p53-dependent and p53-independent apoptosis. Here, we report that CUL7 exerts its antiapoptotic function through p53. CUL7 binds directly to p53, and small interfering RNA-mediated knockdown of CUL7 results in the elevation of p53 protein levels. This antiapoptotic role of CUL7 enables this novel oncogene to cooperate with Myc to drive transformation. Deregulated ectopic expression of c-Myc and CUL7 promotes Rat1a cell growth in soft agar, and knockdown of CUL7 significantly blocks human neuroblastoma SHEP cell growth in an anchorage-independent manner. Furthermore, using public microarray data sets, we show that CUL7 mRNA is significantly overexpressed in non-small cell lung carcinoma and is associated with poor patient prognosis. We provide experimental evidence to show CUL7 is a new oncogene that cooperates with Myc in transformation by blocking Myc-induced apoptosis in a p53-dependent manner.
Kim
Sam S
SS
Division of Cancer Genomics, Ontario Cancer Institute and Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
Shago
Mary
M
Kaustov
Lilia
L
Boutros
Paul C
PC
Clendening
James W
JW
Sheng
Yi
Y
Trentin
Grace A
GA
Barsyte-Lovejoy
Dalia
D
Mao
Daniel Y L
DY
Kay
Robert
R
Jurisica
Igor
I
Arrowsmith
Cheryl H
CH
Penn
Linda Z
LZ
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009857:Oncogenes; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C506299:CUL7 protein, human; D044842:Cullin Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53