Role of the high mobility group A proteins in human lipomas

The HMGA family is comprised of four proteins: HMGA1a, HMGA1b, MIGA1c and H MGA2. The first three proteins are products of the same gene, HMGA1, genera ted through an alternative splicing mechanism. The HMGA proteins are involv ed in the regulation of chromatin structure and HMGA DNA-binding sites have been identified in functional regions of many gene promoters. Rearrangemen ts of the HMGA2 gene have been frequently detected in human benign tumors o f mesenchymal origin including lipomas. 12q13-15 chromosomal translocations involving the HMGA2 gene locus, account for these rearrangements. The HMGA proteins have three AT-hook domains and an acidic C-terminal tail. The HMG A2 modifications consist in the loss of the C-terminal tail and fusion with ectopic sequences. A pivotal role of the HMGA2 rearrangements in the proce ss of lipomagenesis is suggested by experiments showing that transgenic mic e carrying a truncated HMGA2 gene showed a giant phenotype together with ab dominal/pelvic lipomatosis. As HMGA2 null mice showed a great reduction in fat tissue, a positive role of the HMGA2 gene in adipocytic cell proliferat ion is proposed. More recently, similar alterations of the HMGA1 gene have been described. As the block of the HMGA1 protein synthesis induces an incr ease in growth rate of the pre-adipocytic cell line 3T3-L1, we suggest a ne gative role of the HMGA1 proteins in adipocytic cell growth and, therefore, we propose that adipocytic cell growth derives from the balance of the HMG A1 and HMGA2 protein functions.