HMGAs
The mammalian HMGIY/C (HMGAs) are nonhistone chromosomal proteins, that are often referred to as architectural proteins.
They participate in a wide variety of cellular processes including regulation of inducible gene transcription, integration of retroviruses into chromosomes, and the induction of neoplastic transformation and promotion of metastatic progression of cancer cells.
They are characterized by the presence of 3 copies of a conserved DNA-binding peptide motif (AT-hook) that preferentially binds with the minor groove of many AT-rich promoter and enhancer DNA regulatory elements.
Although they possess no substantial secondary structure while free in solution, they organize the framework of the nucleoprotein-DNA transcriptional complex through protein-protein and protein-DNA interactions.
These interactions induce both structural changes in chromatin substrates and the formation of stereospecific complexes called ’enhanceosomes’ on the promoter/enhancer regions of genes whose transcription they regulate.
Members
| HMGA1a | HMGA1b | HMGA1c | HMGA2 |
The HMGA family is comprised of four proteins: HMGA1a, HMGA1b, HMGA1c and HMGA2. The first three proteins are products of the same gene, HMGA1, generated through an alternative splicing mechanism.
The HMGA proteins are involved in the regulation of chromatin structure and HMGA DNA-binding sites have been identified in functional regions of many gene promoters. The HMGA proteins have three AT-hook domains and an acidic C-terminal tail.
As HMGA2 null mice showed a great reduction in fat tissue, a positive role of the HMGA2 gene in adipocytic cell proliferation is proposed.
Pathology
The high mobility group A (HMGA) non-histone chromatin proteins alter chromatin structure and thereby regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias.
Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumours. Conversely, unrearranged HMGA overexpression is a feature of malignant tumours and is also causally related to neoplastic cell transformation.
Rearrangements of the HMGA2 gene have been frequently detected in human benign tumors of mesenchymal origin including lipomas.
12q13-15 chromosomal translocations involving the HMGA2 gene locus, account for these rearrangements.
The HMGA2 modifications consist in the loss of the C-terminal tail and fusion with ectopic sequences.
A pivotal role of the HMGA2 rearrangements in the process of lipomagenesis is suggested by experiments showing that transgenic mice carrying a truncated HMGA2 gene showed a giant phenotype together with abdominal/pelvic lipomatosis.
Similar alterations of the HMGA1 gene have been described. — The block of the HMGA1 protein synthesis induces an increase in growth rate of the pre-adipocytic cell line 3T3-L1.
HMGA1 protein may have a negative role of the in adipocytic cell growth.
References
Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nat Rev Cancer. 2007 Dec;7(12):899-910. PMID: #18004397#
Fedele M, Battista S, Manfioletti G, Croce CM, Giancotti V, Fusco A. Role of the high mobility group A proteins in human lipomas. Carcinogenesis. 2001 Oct;22(10):1583-91. PMID: #11576996#