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Overexpression of Proteins HMGA1 Induces Cell Cycle Deregulation and Apoptosis in Normal Rat Thyroid Cells¹

Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Patologia Cellulare e Molecolare, Universita’ degli Studi di Napoli "Federico II," 80131 Naples, Italy [M. F., G. M. P., M. T. B., S. B., M. D., M. S.]; Istituto Nazionale dei Tumori, Fondazione Giovanni Pascale, 80131 Naples, Italy [G. B., G. V.]; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032 [N. M., D. T.]; and Dipartimento di Medicina Sperimentale e Clinica, Universita’ degli Studi di Catanzaro, 88100 Catanzaro, Italy [A. F.]

The high mobility group (HMG) proteins (HMGA1a, HMGA1b, and HMGA2) bind to DNA and interact with various transcriptional factors. Therefore, they play an important role in chromatin organization. HMGA protein expression is low in normal adult tissues, but abundant during embryonic development and in several experimental and human tumors. Blockage of HMGA expression inhibits the transformation of rat thyroid PC Cl 3 cells treated with oncogene-carrying retroviruses, thus implicating HMGA in rat thyroid transformation. To better understand the role of HMGA and to establish whether its up-regulated expression is sufficient to induce the transformed phenotype, we generated PC Cl 3 cells that overexpress the protein. We demonstrate that HMGA1b protein overexpression does not transform normal rat thyroid PC Cl 3 cells, but it deregulates their cell cycle: cells enter S-phase earlier and the G₂-M transition is delayed. HMGA1-overexpressing cells undergo apoptosis through a pathway involving caspase-3 activation, probably consequent to the conflict between mitogenic pressure and the inability to proceed through the cell cycle. Using various HMGA1b gene mutations, we found that the third AT-hook domain and the acetylation site K60 are the protein regions required for induction of apoptosis in PC Cl 3 cells. In conclusion, although HMGA1 protein overexpression is associated with the malignant phenotype of rat and human thyroid cells, it does not transform normal thyroid cells in culture but leads them to programmed cell death.

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