The HMGA proteins: A myriad of functions (Review)

Abstract

Abstract. The 'high mobility group' HMGA protein family consists of four members: HMGA1a, HMGA1b and HMGA1c, which result from translation of alternative spliced forms of one gene and HMGA2, which is encoded for by another gene. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are architectural transcription factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing the DNA conformation by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors. In this way, they influence a diverse array of normal biological processes including cell growth, proliferation, differentiation and death. Both HMGA1 and HMGA2 are hardly detectable in normal adult tissue but are abundantly and ubiquitously expressed during embryonic development. In malignant epithelial tumors as well as in leukemia, however, expression of HMGA1 is again strongly elevated to embryonic levels thus leading to ectopic expression of (fetal) target genes. HMGA2 overexpression also has a causal role in inducing neoplasia. Besides overexpression of full length HMGA proteins in different tumors, the HMGA genes are often involved in chromosomal rearrangements. Such translocations are mostly detected in benign tumors of mesenchymal origin and are believed to be one of the most common chromosomal rearrangements in human neoplasia. To provide clarity in the abundance of articles on this topic, this review gives a general overview of the nuclear functions and regulation of the HMGA genes and corresponding proteins.

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

“…Rearrangement and resultant overexpression of HMGA2 has been implicated in a variety of human neoplasms. 30 Whereas our data confirmed that all four cases with gains of HMGA2 also expressed the encoded protein, four additional cases without the gain expressed HMGA2 protein as well, indicating alternative mechanisms of upregulating this protein, such as genetic rearrangement. Interestingly, HMGA2 rearrangement or amplification has been implicated in some endometrial polyps.…”

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

“…In contrast, deletions of 7q22, 22q, and 1p frequently co-occurred with other genetic changes and had no major influence on the clustering, suggesting that these changes are involved in tumor progression rather than initiation. Leiomyomas with HMGA1 or HMGA2 alterations displayed similar global expression signatures, supporting the idea that these structurally and evolutionarily related transcription factors have similar functions in tumorigenesis (32). The majority of quadruplenegative leiomyomas clustered into several unique branches, indicating the presence of multiple rare and possibly novel subtypes.…”

Oncocytic Lipoadenoma of the Salivary Gland: A Clinicopathologic Analysis of 7 Cases and Review of the Literature

“…HMGA2 encodes a protein belonging to the non-histone high mobility group protein family. The protein influences an array of cellular processes through regulation of gene transcription [38]. In addition to oncocytic lipoadenoma, HMGA2 gene rearrangements have also been recognized in a number of other neoplasms, including soft tissue lipomas and a subset of salivary gland pleomorphic adenomas [39,40].…”