Disease relevance of HMGA1

• These data indicate that HMGA1 proteins are involved in transcriptional regulation of the BRCA1 gene, and their overexpression may have a role in BRCA1 downregulation observed in aggressive mammary carcinomas [1].
• Finally, we found an inverse correlation between HMGA1 and BRCA1 mRNA and protein expression in human mammary carcinoma cell lines and tissues [1].
• HMGA1 was expressed in both leiomyoma and normal myometria [2].
• This gene expression profile was generated using a well-characterized transgenic human MCF-7 mammary adenocarcinoma cell line in which overexpression of transgenic HMGA1 promotes a transition to a more malignant and metastatic phenotype [3].
• In 17 lung cancer cases, the related bronchial epithelial changes were also studied for HMGA1 and 2 expression [4].

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

• To this end, we explored diagnostic applications of HMGA (HMGA1 and HMGA2) protein immunohistochemistry in comparable groups of synovial sarcoma and malignant peripheral nerve sheath tumors [8].
• Lentivirus-mediated RNA interference of HMGA1 promoted chemosensitivity to gemcitabine in pancreatic adenocarcinoma [9].
• Eighty-eight endometrial specimens from 36 postmenopausal breast cancer patients treated with tamoxifen were investigated cytogenetically and molecularly using fluorescence in situ hybridization with appropriate probes for the HMGIC and HMGIY genes [10].

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

• We have recently demonstrated that the HIPK2 protein interacts with HMGA1 proteins in vitro and in vivo and that HIPK2 exerts a potent inhibitory effect on the cell growth of different normal cell lines [21].
• We have previously shown that HMGA1 enhances the transcriptional activity of promoters containing the estrogen response element (ERE) and increases binding of the estrogen receptor (ER) to ERE [22].
• We found that HMGA1 binds p53 in vitro and in vivo, and both proteins are present in the same complexes bound to the Bax gene promoter [23].
• Electrophoretic mobility shift assay demonstrated that rice HMGB1 can bind synthetic four-way junction (4H) DNA and DNA minicircles efficiently but the binding to 4H can be completed out by HMGA and histone H1 [24].

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

• In this study, we evaluated the immunoreactivity of HMGA1 and HMGA2 in a series of DF and DFSP to determine the possible utility for these markers in the differential diagnosis of these two entities [18].
• Sequence analysis indicates a potential for multiple HMGA1 binding sites within the human KL promoter [28].
• At odds with mice overexpressing a wild-type or a truncated HMGA2 protein, adrenal medullar hyperplasia and pancreatic islet cell hyperplasia frequently occurred and no increase in body size and weight was observed in HMGA1 mice [26].
• Furthermore, preliminary functionality studies utilizing a modified "chromatin" immunoprecipitation protocol revealed that HMGA1 retains its DNA binding capabilities within the mitochondria and associates with the regulatory D-loop region in vivo [29].
• Furthermore, the HMGA1 protein stimulated severalfold the binding of purified ER to the consensus ERE oligonucleotides in gel mobility shift assays and saturation assays [30].

References