| Calpain small-1 modulates Akt/FoxO3A signaling and apoptosis through PP2A. | |
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MedLine Citation:
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PMID: 19029949 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Here, we show that FoxO3A transcription factor is upregulated upon calpain small-1 (CAPNS1) depletion both in mouse embryonic fibroblasts (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-/- fibroblasts. 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 first 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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Authors:
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C Bertoli; T Copetti; E W-F Lam; F Demarchi; C Schneider |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-11-24 |
Journal Detail:
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Title: Oncogene Volume: 28 ISSN: 1476-5594 ISO Abbreviation: Oncogene Publication Date: 2009 Feb |
Date Detail:
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Created Date: 2009-02-05 Completed Date: 2009-02-19 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 721-33 Citation Subset: IM |
Affiliation:
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Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Trieste, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* / genetics Calpain / antagonists & inhibitors, genetics, physiology* Cell Nucleus / metabolism Cells, Cultured Forkhead Transcription Factors / metabolism* Gene Knockdown Techniques Humans Mice Oncogene Protein v-akt / metabolism* Phosphorylation Protein Phosphatase 2 / metabolism, physiology* Protein Transport Signal Transduction / genetics, physiology Starvation / genetics, physiopathology |
| Chemical | |
Reg. No./Substance:
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0/Forkhead Transcription Factors; 0/FoxO3 protein, mouse; EC 2.7.11.1/Oncogene Protein v-akt; EC 3.1.3.16/Protein Phosphatase 2; EC 3.4.22.-/Calpain; EC 3.4.22.-/Capns1 protein, mouse |
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