期刊
CELL DEATH & DISEASE
卷 3, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2012.126
关键词
HMGA proteins; p53; Bcl-2; apoptosis; mitochondria
类别
资金
- Associazione Italiana Ricerca sul Cancro (AIRC) [IG11477, MFAG11702]
- Ministero dell'Universita e della Ricerca Scientifica e Tecnologica (MIUR)
- NOGEC-Naples Oncogenomic Center
- Associazione Partenopea per le Ricerche Oncologiche (APRO)
- FIRC fellowship
The high-mobility group A (HMGA) proteins are a family of non-histone chromatin factors, encoded by the HMGA1 and HMGA2 genes. Several studies demonstrate that HMGA proteins have a critical role in neoplastic transformation, and their overexpression is mainly associated with a highly malignant phenotype, also representing a poor prognostic index. Even though a cytoplasmic localization of these proteins has been previously reported in some highly malignant neoplasias, a clear role for this localization has not been defined. Here, we first confirm the localization of the HMGA1 proteins in the cytoplasm of cancer cells, and then we report a novel mechanism through which HMGA1 inhibits p53-mitochondrial apoptosis by counteracting the binding of p53 to the anti-apoptotic factor Bcl-2. Indeed, we demonstrate a physical and functional interaction between HMGA1 and Bcl-2 proteins. This interaction occurs at mitochondria interfering with the ability of p53 protein to bind Bcl-2, thus counteracting p53-mediated mitochondrial apoptosis. This effect is associated with the inhibition of cytochrome c release and activation of caspases. Consistent with this mechanism, a strong correlation between HMGA1 cytoplasmic localization and a more aggressive histotype of thyroid, breast and colon carcinomas has been observed. Therefore, cytoplasmic localization of HMGA1 proteins in malignant tissues is a novel mechanism of inactivation of p53 apoptotic function. Cell Death and Disease (2012) 3, e383; doi: 10.1038/cddis.2012.126; published online 30 August 2012
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