Fedele M, Pierantoni G M, Berlingieri M T, Battista S, Baldassarre G, Munshi N, Dentice M, Thanos D, Santoro M, Viglietto G, Fusco A
Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Dipartimento di Patologia Cellulare e Molecolare, Università degli Studi di Napoli Federico II, via Pansini 5, 80131 Naples, Italy.
Cancer Res. 2001 Jun 1;61(11):4583-90.
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 G(2)-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.
高迁移率族（HMG）蛋白（HMGA1a、HMGA1b和HMGA2）与DNA结合并与多种转录因子相互作用。因此，它们在染色质组织中发挥重要作用。HMGA蛋白在正常成人组织中表达较低，但在胚胎发育期间以及在一些实验性肿瘤和人类肿瘤中大量表达。阻断HMGA表达可抑制用携带癌基因的逆转录病毒处理的大鼠甲状腺PC Cl 3细胞的转化，从而表明HMGA参与大鼠甲状腺转化。为了更好地理解HMGA的作用并确定其上调表达是否足以诱导转化表型，我们构建了过表达该蛋白的PC Cl 3细胞。我们证明HMGA1b蛋白过表达不会使正常大鼠甲状腺PC Cl 3细胞发生转化，但会使其细胞周期失调：细胞更早进入S期，G（2）-M期转换延迟。过表达HMGA1的细胞通过涉及半胱天冬酶-3激活的途径发生凋亡，这可能是由于促有丝分裂压力与无法完成细胞周期之间的冲突所致。使用各种HMGA1b基因突变，我们发现第三个AT钩结构域和乙酰化位点K60是PC Cl 3细胞中诱导凋亡所需的蛋白区域。总之，尽管HMGA1蛋白过表达与大鼠和人类甲状腺细胞的恶性表型相关，但它不会使培养中的正常甲状腺细胞发生转化，而是导致它们程序性细胞死亡。
