Overexpression of proteins HMGA1 induces cell cycle deregulation and apoptosis in normal rat thyroid cells

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 lo w in normal adult tissues, but abundant during embryonic development and in several experimental and human tumors. Blockage of HMGA expression inhibit s the transformation of rat thyroid PC C1 3 cells treated with oncogene-car rying retroviruses, thus implicating HMGA in rat thyroid transformation. To better understand the role of HMGA and to establish whether its up-regulat ed expression is sufficient to induce the transformed phenotype, we generat ed PC Cl 3 cells that overexpress the protein. We demonstrate that HMGA1b p rotein overexpression does not transform normal rat thyroid PC Cl 3 cells, but it deregulates their cell cycle: cells enter S-phase earlier and the G( 2)-M transition is delayed. HMGA1-overexpressing cells undergo apoptosis th rough a pathway involving caspaseJ activation, probably consequent to the c onflict between mitogenic pressure and the inability to proceed through the cell cycle. Using various HMGA1b gene mutations, we found that the third A T-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 a nd human thyroid cells, it does not transform normal thyroid cells in cultu re but leads them to programmed cell death.