期刊
ONCOGENE
卷 28, 期 5, 页码 721-733出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.425
关键词
CAPNS-1; FoxO3A; apoptosis; PP2A; B56; Akt
资金
- FIRC (Fondazione italiana per la ricerca sul cancro)
- PRIN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale) [2006-prot. 2006053543_003]
- TRANSFOG (Translational and Functinal Onco-Genomics) EU [503438]
- AIRC (Associazione italiana per la ricerca sul cancro) Grant proposal 2007 [Cod. 4752]
- Progetto FAR CT cod. MIUR prog [10036]
Here, we show that FoxO3A transcription factor is upregulated upon calpain small-1 (CAPNS1) depletion both in mouse embryonic. broblasts (MEFs) and in the human mammary carcinoma cell line MCF-7. On starvation, CAPNS1 depletion is associated with a higher rate of FoxO3A dephosphorylation and translocation to the nucleus and to a sharper increase in the levels of p27Kip1 and Bim, the products of two FoxO target genes. Notably, FoxO3A depletion in CAPNS1(-/-) MEFs reduces both the induction of Bim and apoptosis. Both okadaic acid treatment and silencing of the protein phosphatase 2A (PP2A) catalytic subunit can partially reduce starvation-induced FoxO3A activation and apoptosis in CAPNS1(-/-). broblasts. PP2A associates more tightly with Akt in CAPNS1 knockout cells, indicating that PP2A is involved in calpain-mediated FoxO regulation. Finally, we show that PP2A regulatory subunits B56 alpha and gamma are in vitro substrates of calpain, and calpain regulates B56 alpha stability in vivo, suggesting a direct role of calpain in the regulation of PP2A function. In conclusion, for the fist time we report that CAPNS1 interferes with PP2A-Akt interaction consequently affecting FoxO3A-dependent cell death. Calpain inhibition might therefore be exploited as a tool to induce apoptosis in tumors sensitive to FoxO activation.
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