Nuclear degradation of Wilms tumor 1-associating protein and survivin splice variant switching underlie IGF-1-mediated survival.
WTAP (Wilms tumor 1-associating protein) is a recently identified nuclear protein that is essential for mouse embryo development. The Drosophila homolog of WTAP, Fl(2)d, regulates pre-mRNA splicing; however, the role of WTAP in mammalian cells is uncertain. To elucidate a context for WTAP action, we screened growth and survival factors for their effects on WTAP expression in vascular smooth muscle cells (SMCs), a cell type previously found to express WTAP dynamically. This revealed that insulin-like growth factor-1 (IGF-1) uniquely reduced WTAP abundance. This decline in WTAP proved to be necessary for IGF-1 to confer its antiapoptotic properties, which were blocked by transducing the WTAP gene into SMCs. WTAP down-regulation by IGF-1 was mediated by an IGF-1 receptor-phosphatidylinositol 3-kinase-Akt signaling axis that directed WTAP degradation via a nuclear 26 S proteasome. Moreover, by promoting the degradation of WTAP, IGF-1 shifted the pre-mRNA splicing program for the survival factor, survivin, to reduce expression of survivin-2B, which is proapoptotic, and increase expression of survivin, which is antiapoptotic. Knockdown of survivin-2B rescued the ability of IGF-1 to promote survival when WTAP was overexpressed. These data uncover a novel regulatory cascade for human SMC survival based on adjusting the nuclear abundance of WTAP to define the splice variant balance among survivin isoforms.
Small
Theodore W
TW
Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada.
Pickering
J Geoffrey
JG
D017398:Alternative Splicing; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism; D000077022:Survivin
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D007334:Insulin-Like Growth Factor I; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D000077022:Survivin; C107489:BIRC5 protein, human; C419554:WTAP protein, human; C061553:ATP dependent 26S protease