Abstract
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-β (TGF-β). We show that TGF-β 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-β 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-β alone or in cooperation with cancer therapeutic agents. We propose a novel TGF-β/Rb/survivin axis with a putative role in the functional switch of TGF-β from tumor suppressor to tumor promoter.
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Abbreviations
- 3TP-Lux:
-
3TP-luciferase
- CA-ALK5:
-
constitutively active ALK5
- Cdk:
-
cyclin-dependent kinase
- DC-FBS:
-
dextran charcoal-treated FBS
- DMEM/F-12:
-
Dulbecco's modified Eagle's medium/Ham's F-12
- DNAP:
-
DNA pull-down assay
- EMSA:
-
electrophoretic mobility shift assay
- FACS:
-
fluorescence-activated cell sorting
- FBS:
-
fetal bovine serum
- HEK293T:
-
human embryonic kidney cell line 293 inserted with SV40 T antigen
- IAP:
-
inhibitor of apoptosis
- P-Rb:
-
phosphorylated Rb
- P-Smad:
-
phosphorylated Smad
- Rb:
-
retinoblastoma protein
- R-Smad:
-
receptor-regulated Smad
- SAC:
-
a 32-bp survivin promoter region (−50/−19) containing SBE2, CDE and CHR elements
- SBE:
-
Smad-binding element
- shRNA:
-
short-hairpin RNA
- TβRI:
-
TGF-β receptor type I
- TβRII:
-
TGF-β receptor type II
- TGF-β:
-
transforming growth factor-β
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Acknowledgements
This research was supported by the Gene Expression and Genotyping Facility, the Flow Cytometry Core Facility of the Case Comprehensive Cancer Center (P30 CA43703). Grant support: NCI grants R01CA092102 and R01CA102074 (to D Danielpour).
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Yang, J., Song, K., Krebs, T. et al. Rb/E2F4 and Smad2/3 link survivin to TGF-β-induced apoptosis and tumor progression. Oncogene 27, 5326–5338 (2008). https://doi.org/10.1038/onc.2008.165
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DOI: https://doi.org/10.1038/onc.2008.165
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