Abstract
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.
Highlights
HMGA1a, HMGA1b and HMGA1c, derived from an alternative splicing of the same gene, HMGA1,1,2 and HMGA2, encoded by the homonymous gene.[3]
We have previously demonstrated that overexpression of high-mobility group A (HMGA) proteins is required for cell transformation, as the blockage of their synthesis prevents tumorigenic transformation of rat thyroid cells by murine-transforming retroviruses,[16] and infection with a recombinant adenovirus carrying the HMGA1b complementary DNA in antisense orientation led several carcinoma cell lines to death.[17]
HMGA1b recombinant protein displaced B-cell lymphoma gene-2 (Bcl-2) from the binding to p53. These findings demonstrate that HMGA1b directly interferes with the p53/Bcl-2 binding
Summary
HMGA1a, HMGA1b and HMGA1c, derived from an alternative splicing of the same gene, HMGA1,1,2 and HMGA2, encoded by the homonymous gene.[3]. HMGA proteins do not have transcriptional activity per se, by interacting with the transcriptional machinery, they alter the chromatin structure and, thereby, regulate the transcriptional activity of several genes.[4,5] The expression of HMGA proteins is high during embryogenesis and low or undetectable in normal adult tissues.[6,7] high HMGA expression has been observed in human malignant neoplasias, including thyroid,[8] colon,[9] prostate,[10] pancreas,[11] cervix,[12] ovary,[13] and breast[14] carcinomas Their overexpression is mainly associated with a highly malignant phenotype, representing a poor prognostic index, as HMGA overexpression often correlates with the presence of metastases, and with a reduced survival.[15] A functional role of this aberrant HMGA overexpression in cancer has been previously demonstrated by in vitro and in vivo studies.
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