title: CUL7 is a novel antiapoptotic oncogene.
abstract: 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.
authors.affiliation: Division of Cancer Genomics, Ontario Cancer Institute and Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Kim
authors.forename: Mary
authors.initials: M
authors.lastname: Shago
authors.forename: Lilia
authors.initials: L
authors.lastname: Kaustov
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.forename: James W
authors.initials: JW
authors.lastname: Clendening
authors.forename: Yi
authors.initials: Y
authors.lastname: Sheng
authors.forename: Grace A
authors.initials: GA
authors.lastname: Trentin
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.forename: Daniel Y L
authors.initials: DY
authors.lastname: Mao
authors.forename: Robert
authors.initials: R
authors.lastname: Kay
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Linda Z
authors.initials: LZ
authors.lastname: Penn
mesh_terms: 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
chemical_list: 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