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Gene Review

HMGA1  -  high mobility group AT-hook 1

Homo sapiens

Synonyms: HMG-I(Y), HMG-R, HMGA1A, HMGIY, High mobility group AT-hook protein 1, ...
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Disease relevance of HMGA1


High impact information on HMGA1

  • Our results identify a component of the senescence machinery that contributes to heterochromatin formation and imply that HMGA proteins also act in tumor suppressor networks [5].
  • Surprisingly, we show that the High-Mobility Group A (HMGA) proteins, which can promote tumorigenesis, accumulate on the chromatin of senescent fibroblasts and are essential structural components of SAHFs [5].
  • Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity [6].
  • Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice [6].
  • HMGA proteins are moderately sequence-specific, and help build enhanceosomes by interacting with partner proteins and binding stably to the minor groove of DNA; their acetylation/deacetylation signal enhanceosome assembly or disassembly [7].

Chemical compound and disease context of HMGA1


Biological context of HMGA1

  • Either 5' or 3' deletion variants of the 1,600 bp promoter/luciferase reporter strongly decreased luciferase activity, suggesting that, more than a single site, the cooperative function of multiple cis-acting elements mediates direct HMGA1 transactivation by MYCN [11].
  • Indeed, MYCN transfection induced HMGA1 expression in several neuroblastoma cell lines [11].
  • MYCN cotransfection activated a promoter/luciferase reporter containing a 1,600 bp region surrounding the first three transcription start sites of the human HMGA1 and eight imperfect E-boxes [11].
  • Employing both stably transfected lines of human MCF7 cells containing tetracycline-regulated HMGA1 transgenes and primary Hs578T tumor cells, which naturally overexpress HMGA1 proteins, we have shown that cells overexpressing HMGA1a protein exhibit increased UV sensitivity [12].
  • The overexpression of transgenic HMGA1 proteins in cells results in neoplastic transformation and promotes progression to malignant cellular phenotypes [3].

Anatomical context of HMGA1

  • Nuclear immunostaining for HMGA1 and 2 proteins also occurred in hyperplastic, metaplastic, and dysplastic bronchial epithelium [4].
  • We have demonstrated previously that 3T3-L1 adipocytic differentiation is associated with increased HMGA1 protein levels, and that the block of HMGA1 synthesis dramatically increases the growth rate of 3T3-L1 cells and suppresses adipocytic differentiation [13].
  • Overexpression of proteins HMGA1 induces cell cycle deregulation and apoptosis in normal rat thyroid cells [14].
  • The HMGA1 protooncogene codes for two closely related isoform proteins, HMGA1a and HMGA1b, and causes cancerous cellular transformation when overexpressed in either transgenic mice or "normal" cultured cell lines [15].
  • Here, we report that high expression levels of HMGA1 proteins in MCF-7 or mouse embryonic stem cells results in diminished BRCA1 expression and enhanced sensitivity to Cisplatin and Bleomycin [16].

Associations of HMGA1 with chemical compounds

  • In addition, MYCN constitutive expression abolishes HMGA1 repression by RA [11].
  • To check if HMGA expression is under control of such elements we performed luciferase assays with several HMGA2 and HMGA1 3'UTRs of different length [17].
  • We conclude that HMGA1 and HMGA2 expression can be used to distinguish DF from DFSP with a degree of accuracy that is fully equivalent to that of Factor XIIIa and CD34 [18].
  • Interestingly, RA increases HMGA1 expression in RA-resistant NB cells but inhibits it in cells undergoing RA-induced growth inhibition and neuronal differentiation [19].
  • The role of phosphatidylinositol-3 kinase (PI3K)/Akt in mediating HMGA1-dependent invasiveness was elucidated by a specific PI3K inhibitor (LY294002) and constitutively active and dominant-negative Akt adenoviral constructs [20].

Physical interactions of HMGA1


Regulatory relationships of HMGA1

  • The HMGA1 protein stimulated binding and transcriptional activity by a factor of about 2-fold compared to the wild-type ER and both the N- and C-terminal ER deleted domains, but had no effect when both domains were deleted [22].
  • In fact, we found that Hmga1-/- ES cells overexpress GATA-1 and that HMGA1 proteins directly control GATA-1 transcription [25].

Other interactions of HMGA1

  • Experiments showed that an up to 12-fold increase in luciferase activity is obtained by the truncation of the 3'UTRs suggesting that the expression of HMGA2 and HMGA1 is controlled by negatively acting regulatory elements within their 3'UTR [17].
  • The functional interaction between HMGA1 and the estrogen receptor requires either the N- or the C-terminal domain of the receptor [22].
  • Conversely, forced HMGA1 overexpression resulted in significant increases in cellular invasiveness; in cellular MMP-9 activity, mRNA levels, and promoter activity; and in Akt phosphorylation at Ser(473) [20].
  • Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas [26].
  • Moreover, the lack of the neoplastic phenotype in the virus-infected thyroid cells carrying the HMGA1 antisense construct correlates with the absence of induction of AP-1 transcriptional activity [27].

Analytical, diagnostic and therapeutic context of HMGA1


  1. Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Baldassarre, G., Battista, S., Belletti, B., Thakur, S., Pentimalli, F., Trapasso, F., Fedele, M., Pierantoni, G., Croce, C.M., Fusco, A. Mol. Cell. Biol. (2003) [Pubmed]
  2. Aberrant expression of HMGA2 in uterine leiomyoma associated with loss of TSC2 tumor suppressor gene function. Hunter, D.S., Klotzbücher, M., Kugoh, H., Cai, S.L., Mullen, J.P., Manfioletti, G., Fuhrman, U., Walker, C.L. Cancer Res. (2002) [Pubmed]
  3. High-mobility group A1a protein regulates Ras/ERK signaling in MCF-7 human breast cancer cells. Treff, N.R., Pouchnik, D., Dement, G.A., Britt, R.L., Reeves, R. Oncogene (2004) [Pubmed]
  4. Increased expression of high mobility group A proteins in lung cancer. Sarhadi, V.K., Wikman, H., Salmenkivi, K., Kuosma, E., Sioris, T., Salo, J., Karjalainen, A., Knuutila, S., Anttila, S. J. Pathol. (2006) [Pubmed]
  5. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Narita, M., Narita, M., Krizhanovsky, V., Nuñez, S., Chicas, A., Hearn, S.A., Myers, M.P., Lowe, S.W. Cell (2006) [Pubmed]
  6. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Foti, D., Chiefari, E., Fedele, M., Iuliano, R., Brunetti, L., Paonessa, F., Manfioletti, G., Barbetti, F., Brunetti, A., Croce, C.M., Fusco, A., Brunetti, A. Nat. Med. (2005) [Pubmed]
  7. HMGB proteins and gene expression. Agresti, A., Bianchi, M.E. Curr. Opin. Genet. Dev. (2003) [Pubmed]
  8. HMGA proteins in malignant peripheral nerve sheath tumor and synovial sarcoma: preferential expression of HMGA2 in malignant peripheral nerve sheath tumor. Hui, P., Li, N., Johnson, C., De Wever, I., Sciot, R., Manfioletti, G., Tallini, G. Mod. Pathol. (2005) [Pubmed]
  9. Lentivirus-Mediated RNA Interference of HMGA1 Promotes Chemosensitivity to Gemcitabine in Pancreatic Adenocarcinoma. Liau, S.S., Ashley, S.W., Whang, E.E. J. Gastrointest. Surg. (2006) [Pubmed]
  10. Genomic changes in endometrial polyps associated with tamoxifen show no evidence for its action as an external carcinogen. Dal Cin, P., Timmerman, D., Van den Berghe, I., Wanschura, S., Kazmierczak, B., Vergote, I., Deprest, J., Neven, P., Moerman, P., Bullerdiek, J., Van den Berghe, H. Cancer Res. (1998) [Pubmed]
  11. High mobility group A1 is a molecular target for MYCN in human neuroblastoma. Giannini, G., Cerignoli, F., Mellone, M., Massimi, I., Ambrosi, C., Rinaldi, C., Dominici, C., Frati, L., Screpanti, I., Gulino, A. Cancer Res. (2005) [Pubmed]
  12. Inhibition of nucleotide excision repair by high mobility group protein HMGA1. Adair, J.E., Kwon, Y., Dement, G.A., Smerdon, M.J., Reeves, R. J. Biol. Chem. (2005) [Pubmed]
  13. A truncated HMGA1 gene induces proliferation of the 3T3-L1 pre-adipocytic cells: a model of human lipomas. Pierantoni, G.M., Battista, S., Pentimalli, F., Fedele, M., Visone, R., Federico, A., Santoro, M., Viglietto, G., Fusco, A. Carcinogenesis (2003) [Pubmed]
  14. Overexpression of proteins HMGA1 induces cell cycle deregulation and apoptosis in normal rat thyroid cells. Fedele, M., Pierantoni, G.M., Berlingieri, M.T., Battista, S., Baldassarre, G., Munshi, N., Dentice, M., Thanos, D., Santoro, M., Viglietto, G., Fusco, A. Cancer Res. (2001) [Pubmed]
  15. Dynamic and differential in vivo modifications of the isoform HMGA1a and HMGA1b chromatin proteins. Edberg, D.D., Adkins, J.N., Springer, D.L., Reeves, R. J. Biol. Chem. (2005) [Pubmed]
  16. HMGA1 protein expression sensitizes cells to cisplatin-induced cell death. Baldassarre, G., Belletti, B., Battista, S., Nicoloso, M.S., Pentimalli, F., Fedele, M., Croce, C.M., Fusco, A. Oncogene (2005) [Pubmed]
  17. The expression of HMGA genes is regulated by their 3'UTR. Borrmann, L., Wilkening, S., Bullerdiek, J. Oncogene (2001) [Pubmed]
  18. Differential expression of HMGA1 and HMGA2 in dermatofibroma and dermatofibrosarcoma protuberans: potential diagnostic applications, and comparison with histologic findings, CD34, and factor XIIIa immunoreactivity. Li, N., McNiff, J., Hui, P., Manfioletti, G., Tallini, G. The American Journal of dermatopathology. (2004) [Pubmed]
  19. HMGA molecules in neuroblastic tumors. Cerignoli, F., Ambrosi, C., Mellone, M., Assimi, I., di Marcotullio, L., Gulino, A., Giannini, G. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  20. HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma. Liau, S.S., Jazag, A., Whang, E.E. Cancer Res. (2006) [Pubmed]
  21. The homeodomain-interacting protein kinase 2 gene is expressed late in embryogenesis and preferentially in retina, muscle, and neural tissues. Pierantoni, G.M., Bulfone, A., Pentimalli, F., Fedele, M., Iuliano, R., Santoro, M., Chiariotti, L., Ballabio, A., Fusco, A. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  22. The functional interaction between HMGA1 and the estrogen receptor requires either the N- or the C-terminal domain of the receptor. Massaad-Massade, L., Tacine, R., Dulauroy, S., Reeves, R., Barouki, R. FEBS Lett. (2004) [Pubmed]
  23. High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity. Pierantoni, G.M., Rinaldo, C., Esposito, F., Mottolese, M., Soddu, S., Fusco, A. Cell Death Differ. (2006) [Pubmed]
  24. Rice HMGB1 protein recognizes DNA structures and bends DNA efficiently. Wu, Q., Zhang, W., Pwee, K.H., Kumar, P.P. Arch. Biochem. Biophys. (2003) [Pubmed]
  25. Loss of Hmga1 gene function affects embryonic stem cell lympho-hematopoietic differentiation. Battista, S., Pentimalli, F., Baldassarre, G., Fedele, M., Fidanza, V., Croce, C.M., Fusco, A. FASEB J. (2003) [Pubmed]
  26. Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Fedele, M., Pentimalli, F., Baldassarre, G., Battista, S., Klein-Szanto, A.J., Kenyon, L., Visone, R., De Martino, I., Ciarmiello, A., Arra, C., Viglietto, G., Croce, C.M., Fusco, A. Oncogene (2005) [Pubmed]
  27. Thyroid cell transformation requires the expression of the HMGA1 proteins. Berlingieri, M.T., Pierantoni, G.M., Giancotti, V., Santoro, M., Fusco, A. Oncogene (2002) [Pubmed]
  28. Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells. Treff, N.R., Dement, G.A., Adair, J.E., Britt, R.L., Nie, R., Shima, J.E., Taylor, W.E., Reeves, R. Oncogene (2004) [Pubmed]
  29. Dynamic mitochondrial localization of nuclear transcription factor HMGA1. Dement, G.A., Treff, N.R., Magnuson, N.S., Franceschi, V., Reeves, R. Exp. Cell Res. (2005) [Pubmed]
  30. HMGA1 enhances the transcriptional activity and binding of the estrogen receptor to its responsive element. Massaad-Massade, L., Navarro, S., Krummrei, U., Reeves, R., Beaune, P., Barouki, R. Biochemistry (2002) [Pubmed]
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