Caspase 2-mediated tumor suppression involves survivin gene silencing.
One of the pivotal functions of endogenous tumor suppression is to oppose aberrant cell survival, but the molecular requirements of this process are not completely understood. Here, we show that caspase 2, a death effector with largely unknown functions, represses transcription of the survivin gene, a general regulator of cell division and cytoprotection in tumors. This pathway involves caspase 2 proteolytic cleavage of the nuclear factor kappaB (NFkappaB) activator, RIP1. In turn, loss of RIP1 abolishes transcription of NFkappaB target genes, including survivin, resulting in deregulated mitotic transitions, enhanced apoptosis and suppression of tumorigenicity in vivo. Therefore, caspase 2 functions as an endogenous inhibitor of NFkappaB-dependent cell survival and this mechanism may contribute to tumor suppression in humans.
Guha
M
M
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01609, USA.
Xia
F
F
Raskett
C M
CM
Altieri
D C
DC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D000077022:Survivin; D014162:Transfection
C119724:AGFG1 protein, human; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D000077022:Survivin; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases