Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression.
Survivin is a prosurvival protein overexpressed in many cancers through mechanisms that remain poorly explored, and is implicated in control of tumor progression and resistance to cancer chemotherapeutics. Here, we report a critical role for survivin in the induction of apoptosis by transforming growth factor-beta (TGF-beta). We show that TGF-beta rapidly downregulates survivin expression in prostate epithelial cells, through a unique mechanism of transcriptional suppression involving Smads 2 and 3, Rb/E2F4, and the cell-cycle repressor elements CDE and CHR. This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter. Viral-mediated gene delivery experiments, involving overexpressing or silencing survivin, reveal critical roles of survivin in apoptosis induced by TGF-beta alone or in cooperation with cancer therapeutic agents. We propose a novel TGF-beta/Rb/survivin axis with a putative role in the functional switch of TGF-beta from tumor suppressor to tumor promoter.
Yang
J
J
Division of General Medical Sciences-Oncology, Case School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Song
K
K
Krebs
T L
TL
Jackson
M W
MW
Danielpour
D
D
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D020218:Response Elements; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D016160:Retinoblastoma Protein; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D000077022:Survivin; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I