Disease relevance of HMGA2

• Concomitantly, HMGA2 protein, which was completely absent in normal myometria, was expressed in 16 of 19 Eker leiomyomas [1].
• RNA expression of HMGA1a and b isoforms and of HMGA2 was determined by real-time semi-quantitative RT-PCR in 23 lung carcinomas [2].
• Repression of HMGA2 Gene Expression by Human Cytomegalovirus Involves the IE2 86-Kilodalton Protein and Is Necessary for Efficient Viral Replication and Inhibition of Cyclin A Transcription [3].
• Since HMGA2 is important for cell proliferation and differentiation, particularly during embryogenesis, it is possible that the repression of HMGA2 expression during fetal development could contribute to the specific birth defects in HCMV-infected neonates [3].
• Increased nuclear expression of HMGA1 and 2 correlated with poor survival (for adenocarcinomas, HMGA1, p=0.006; HMGA2, p=0.05) [2].
• Ectopic expression of let-7 reduced HMGA2 and cell proliferation in a lung cancer cell [4].
• HMGA2 was not expressed in sections of normal adult lung or other proliferative interstitial lung diseases, indicating that the expression of HMGA2 in LAM represents aberrant gene activation and is not due solely to an increase in cellular proliferation [5].
• Overexpression of HMGA2 is associated with metastasis and unequivocally occurred in parallel with reduced survival rates of patients with CRC [6].

Psychiatry related information on HMGA2

• We also observed that blood adipsin concentrations can vary as a function of feeding or adiposity, in that they tend to be mildly elevated in obese individuals or mildly reduced in individuals with total lipo-atrophy, cachexia related to AIDS and anorexia nervosa [7].

High impact information on HMGA2

• These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers [8].
• Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours [9].
• Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains [10].
• Chimeric transcripts were isolated from two lipomas in which HMGI-C DNA-binding domains (AT hook motifs) are fused to either a LIM or an acidic transactivation domain [10].
• These results, identifying a gene rearranged in a benign neoplastic process that does not proceed to a malignancy, suggest a role for HMGI-C in adipogenesis and mesenchyme differentiation [10].

Chemical compound and disease context of HMGA2

• HMGA proteins in malignant peripheral nerve sheath tumor and synovial sarcoma: preferential expression of HMGA2 in malignant peripheral nerve sheath tumor [11].
• Here, we reported a correlation between increased HMGA2 expression and enhanced chemosensitivity towards topoisomerase II inhibitor, doxorubicin, in breast cancer cells [12].
• Upregulation of some factors (HMGA2, sex steroid receptor cofactors, proteins in insulin pathway, and CD24) were identified in a group of patients in their later forties, were associated with large fibroids, and were weakly affected by the SSH status (illustrated by endometrial phases and menopause) [13].
• 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 [14].
• HMGI(Y) and HMGI-C genes are expressed in neuroblastoma cell lines and tumors and affect retinoic acid responsiveness [15].

Biological context of HMGA2

• Transcriptional activation of the cyclin A gene by the architectural transcription factor HMGA2 [16].
• These data identify the cyclin A gene as a cellular target for HMGA2 and, for the first time, suggest a mechanism for HMGA2-dependent cell cycle regulation [16].
• The pattern of rearrangements suggests dysregulated expression of HMGA2, most often by translocation of chromosome 14 sequence 5' to this gene [17].
• Aberrant expression of HMGA2 in uterine leiomyoma associated with loss of TSC2 tumor suppressor gene function [1].
• Furthermore, a functional polymorphic dinucleotide repeat (TCTCT(TC)(n)) 500 bp upstream of the ATG translational start codon was found to regulate strongly the human HMGA2 promoter with an activation pattern that correlates to its TC-repeat length [18].

Anatomical context of HMGA2

• No structural alterations were observed at the HMGA2 locus in either primary rat leiomyomas or leiomyoma-derived cell lines that expressed HMGA2 [1].
• These data support a role for HMGA2 in the development of smooth muscle neoplasms and suggest HMGA2 expression is a point of convergence between the human disease and the Eker rat model [1].
• HMGA2 is expressed only in a subset of ex vivo neuroblastoma (NB) tumors and in the embryonic adrenal gland, but it is undetectable in the adult adrenal gland, suggesting that its anomalous expression might be associated with NB tumorigenesis and/or tumor progression [19].
• The lipoma preferred partner (LPP) gene is the most frequent translocation partner of HMGA2 in a subgroup of lipomas, which are benign tumors of adipose tissue [20].
• HMGA2 is an architectural transcriptional factor that is expressed in the undifferentiated mesenchyme and initiates mesenchymal tumor formation [21].

Associations of HMGA2 with chemical compounds

• The HMGA2 protein belongs to the HMGA family of architectural transcription factors, which play an important role in chromatin organization [16].
• These findings should contribute to a greater understanding of the role of HMGA2 in promoting tumorigenesis and conveying (chemo)sensitivity towards doxorubicin and other related double-strand breaks [12].
• Moreover, this HMGA2-dependent enhancement of cytotoxicity is further extended to other double-strand breaks elicited by cisplatin and X-ray irradiation and is not restricted to one cell type [12].
• Notably, HMGA2 enhances doxorubicin-elicited cell cycle delay in sub-G1 and G2-M and augments cell cycle dysregulation on cotreatment of doxorubicin and caffeine [12].
• We then evaluated the expression of the PPARalpha, PPARgamma2, HMGA2, leptin and TSHr genes before and after 24 h of fenofibrate treatment, using semiquantitative and real-time PCR [22].

Physical interactions of HMGA2

• Our results provide the first insights into how HMGA2 and its aberrant forms bind and regulate the ERCC1 promoter [23].
• These transcripts encode fusion proteins containing RAD51L1 nucleotide binding domains and the HMGIC protein lacking the N-terminal AT hook motifs [24].

Regulatory relationships of HMGA2

• 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 [25].
• Furthermore, the regulatory effect of HMGA2 was confirmed by luciferase promoter assays showing that ERCC1 promoter activity is down-regulated by all investigated HMGA2 forms, with the most striking effect exerted by DeltaHMGA2 [23].
• In normal salivary gland tissue WIF1 is expressed at a high level and HMGA2 is not expressed [26].

Other interactions of HMGA2

• RAD51L1-HMGA2 transcripts were not detected [17].
• 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 [25].
• In addition, chromatin immunoprecipitation experiments show that HMGA2 associates with the cyclin A promoter only when the gene is transcriptionally activated [16].
• Overexpression of HMGA2-LPP fusion transcripts promotes expression of the alpha 2 type XI collagen gene [27].
• Differential expression of HMGA1 and HMGA2 in dermatofibroma and dermatofibrosarcoma protuberans: potential diagnostic applications, and comparison with histologic findings, CD34, and factor XIIIa immunoreactivity [28].

Analytical, diagnostic and therapeutic context of HMGA2

• Molecular dissection of the architectural transcription factor HMGA2 [29].
• 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 [11].
• Real-time PCR analysis showed that HMGA2-LPP and COL11A2 were co-expressed [27].
• 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 [28].
• By dual-color interphase fluorescence in situ hybridization analysis using HMGA2-specific PACs and BACs, we found that the HMGA2 locus was amplified in seven of the eight prolactinoma samples examined [30].

References