title: Depletion of K-Ras promotes proteasome degradation of survivin.
abstract: Mutant K-Ras and survivin both contribute to oncogenesis, but little is known about K-Ras requirement for the maintenance of the high levels of survivin in human tumors. Here we demonstrate that K-Ras depletion significantly decreases survivin levels in human cancer cells that harbor mutant but not wild type K-Ras. K-Ras depletion attenuates both basal and drug-induced survivin levels. The mechanism by which K-Ras depletion decreases survivin levels is through ubiquitination and proteasomal degradation of survivin and is independent of survivin-Thr-34 phosphorylation. Depletion of RalA and RalB, but not Raf-1, Akt1 and Akt2, decreases survivin levels, suggesting that K-Ras may regulate survivin stability through its RalGDS/Ral but not PI3K/Akt and Raf-1/Mek effector pathways. Furthermore, the ability of mutant K-Ras to induce anchorage-independent growth, invasion and survival is compromised by depletion of survivin. These studies suggest that mutant K-Ras contributes to the maintenance of the aberrantly high levels of survivin in tumors by regulating its stability, and that the ability of mutant K-Ras to induce malignant transformation is, at least in part, dependent on these high levels of survivin.
authors: Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors: Awet
authors: A
authors: Tecleab
authors: Saïd M
authors: SM
authors: Sebti
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D000077022:Survivin; D054875:Ubiquitination; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020726:ral Guanine Nucleotide Exchange Factor / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C483163:Ralb protein, human; D000077022:Survivin; D020726:ral Guanine Nucleotide Exchange Factor; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D046988:Proteasome Endopeptidase Complex; C492198:RALA protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020725:ral GTP-Binding Proteins
keywords: K-Ras; apoptosis; cancer; proteasome; protein degradation; survivin