HMGA2
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| Location (UCSC) | Chr 12: 65.82 – 65.97 Mb | n/a | |||||||
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High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the HMGA2 gene.[3][4][5]
Function
This gene encodes a protein that belongs to the non-histone chromosomal high-mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhanceosome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with lipomas suggests a role in adipogenesis and mesenchymal differentiation. A gene knock-out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[5]
The expression of HMGA2 in adult tissues is commonly associated with both malignant and benign tumor formation, as well as certain characteristic cancer-promoting mutations. Homologous proteins with highly conserved sequences are found in other mammalian species, including lab mice (
HMGA2 contains three basic
Regulation by let-7
Clinical significance
Relationship with cancer
Heightened expression of HMGA2 is found in a variety of human cancers, but the precise mechanism by which HMGA2 contributes to the formation of cancer is unknown.
A very common finding in HMGA2-high cancers is the under-expression of let-7.[14] This is not unexpected, given let-7's natural role in the regulation of HMGA2. However, many cancers are found with normal levels of let-7 that are also HMGA2 high. Many of these cancers express the normal HMGA2 protein, but the mature mRNA transcript is truncated, missing a portion of the 3'UTR that contains the critical let-7 complementary regions. Without these, let-7 is unable to bind to HMGA2 mRNA, and, thus, is unable to repress it. The truncated mRNAs may arise from a chromosomal translocation that results in loss of a portion of the HMGA2 gene.[10]
ERCC1
Overexpressed HMGA2 may play a role in the frequent repression of ERCC1 in cancers. The let-7a miRNA normally represses the HMGA2 gene, and in normal adult tissues, almost no HMGA2 protein is present.[15] (See also Let-7 microRNA precursor.) Reduction or absence of let-7a miRNA allows high expression of the HMGA2 protein. As shown by Borrmann et al.,[16] HMGA2 targets and modifies the chromatin architecture at the ERCC1 gene, reducing its expression. These authors noted that repression of ERCC1 (by HGMA2) can reduce DNA repair, leading to increased genome instability.
ERCC1 protein expression is reduced or absent in 84% to 100% of human colorectal cancers.[17][18] ERCC1 protein expression was also reduced in a diet-related mouse model of colon cancer.[19] As indicated in the ERCC1 article, however, two other epigenetic mechanisms of repression of ERCC1 also may have a role in reducing expression of ERCC1 (promoter DNA methylation and microRNA repression).
Chromatin immunoprecipitation
Genome-wide analysis of HMGA2 target genes was performed by chromatin immunoprecipitation in a gastric cell line with overexpressed HMGA2, and 1,366 genes were identified as potential targets.[20] The pathways they identified as associated with malignant neoplasia progression were the adherens junction pathway, MAPK signaling pathway, Wnt signaling pathway, p53 signaling pathway, VEGF signaling pathway, Notch signaling pathway, and TGF beta signaling pathway.
Non-homologous end joining DNA repair
Overexpression of HMGA2 delayed the release of DNA-PKcs (needed for non-homologous end joining DNA repair) from double strand break sites. Overexpression of HMGA2 alone was sufficient to induce chromosomal aberrations, a hallmark of deficiency in NHEJ-mediated DNA repair. These properties implicate HMGA2 in the promotion of genome instability and tumorigenesis.[21] showed that
Base excision repair pathway
HMGA2 protein can cleave DNA containing apurinic/apyrimidinic (AP) sites (is an AP lyase). In addition, this protein also possesses the related 5’-deoxyribosyl phosphate (dRP) lyase activity. An interaction between human AP endonuclease 1 and HMGA2 in cancer cells has been demonstrated indicating that HMGA2 can be incorporated into the cellular base excision repair (BER) machinery. Increased expression of HMGA2 increased BER, and allowed cells with increased HMGA2 to be resistant to hydroxyurea, a chemotherapeutic agent for solid tumors.[22]
Interactions
HMGA2 has been shown to
The transport of HMGA2 to the nucleus is mediated by an interaction between its second AT-hook and
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000149948 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 8824803.
- S2CID 42615999.
- ^ a b "Entrez Gene: HMGA2 high mobility group AT-hook 2".
- PMID 12082634.
- ^ PMID 18371414.
- ^ PMID 17324944.
- PMID 19070572.
- ^ PMID 17322030.
- ^ PMID 16969098.
- S2CID 30541611.
- ^ PMID 16061642.
- PMID 17600087.
- PMID 18413822.
- PMID 14627817.
- PMID 22494821.
- PMID 24603753.
- PMID 25024814.
- S2CID 15777147.
- PMID 19549901.
- PMID 19465398.
- PMID 11390395.
- S2CID 39605320.
Further reading
- Pedeutour F, Ligon AH, Morton CC (November 1999). "[Genetics of uterine leiomyomata]". Bulletin du Cancer. 86 (11): 920–8. PMID 10586108.
- Reeves R, Beckerbauer L (May 2001). "HMGI/Y proteins: flexible regulators of transcription and chromatin structure". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1519 (1–2): 13–29. PMID 11406267.
- Manfioletti G, Giancotti V, Bandiera A, Buratti E, Sautière P, Cary P, et al. (December 1991). "cDNA cloning of the HMGI-C phosphoprotein, a nuclear protein associated with neoplastic and undifferentiated phenotypes". Nucleic Acids Research. 19 (24): 6793–7. PMID 1762909.
- Chau KY, Patel UA, Lee KL, Lam HY, Crane-Robinson C (November 1995). "The gene for the human architectural transcription factor HMGI-C consists of five exons each coding for a distinct functional element". Nucleic Acids Research. 23 (21): 4262–6. PMID 7501444.
- Schoenmakers EF, Mols R, Wanschura S, Kools PF, Geurts JM, Bartnitzke S, et al. (October 1994). "Identification, molecular cloning, and characterization of the chromosome 12 breakpoint cluster region of uterine leiomyomas". Genes, Chromosomes & Cancer. 11 (2): 106–18. S2CID 25942810.
- Ashar HR, Fejzo MS, Tkachenko A, Zhou X, Fletcher JA, Weremowicz S, et al. (July 1995). "Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains". Cell. 82 (1): 57–65. S2CID 15593143.
- Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJ (August 1995). "Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours". Nature Genetics. 10 (4): 436–44. S2CID 29935721.
- Patel UA, Bandiera A, Manfioletti G, Giancotti V, Chau KY, Crane-Robinson C (May 1994). "Expression and cDNA cloning of human HMGI-C phosphoprotein". Biochemical and Biophysical Research Communications. 201 (1): 63–70. PMID 8198613.
- Ashar HR, Cherath L, Przybysz KM, Chada K (January 1996). "Genomic characterization of human HMGIC, a member of the accessory transcription factor family found at translocation breakpoints in lipomas". Genomics. 31 (2): 207–14. PMID 8824803.
- Ishwad CS, Shriver MD, Lassige DM, Ferrell RE (January 1997). "The high mobility group I-C gene (HMGI-C): polymorphism and genetic localization". Human Genetics. 99 (1): 103–5. S2CID 42615999.
- Petit MM, Swarts S, Bridge JA, Van de Ven WJ (October 1998). "Expression of reciprocal fusion transcripts of the HMGIC and LPP genes in parosteal lipoma". Cancer Genetics and Cytogenetics. 106 (1): 18–23. PMID 9772904.
- Schoenmakers EF, Huysmans C, Van de Ven WJ (January 1999). "Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas". Cancer Research. 59 (1): 19–23. PMID 9892177.
- Gattas GJ, Quade BJ, Nowak RA, Morton CC (August 1999). "HMGIC expression in human adult and fetal tissues and in uterine leiomyomata". Genes, Chromosomes & Cancer. 25 (4): 316–22. S2CID 42957480.
- Schwanbeck R, Manfioletti G, Wiśniewski JR (January 2000). "Architecture of high mobility group protein I-C.DNA complex and its perturbation upon phosphorylation by Cdc2 kinase". The Journal of Biological Chemistry. 275 (3): 1793–801. PMID 10636877.
- Piekielko A, Drung A, Rogalla P, Schwanbeck R, Heyduk T, Gerharz M, et al. (January 2001). "Distinct organization of DNA complexes of various HMGI/Y family proteins and their modulation upon mitotic phosphorylation". The Journal of Biological Chemistry. 276 (3): 1984–92. PMID 11034995.
- Rogalla P, Lemke I, Kazmierczak B, Bullerdiek J (December 2000). "An identical HMGIC-LPP fusion transcript is consistently expressed in pulmonary chondroid hamartomas with t(3;12)(q27-28;q14-15)". Genes, Chromosomes & Cancer. 29 (4): 363–6. S2CID 35883889.
- Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK (August 2001). "Requirement for high mobility group protein HMGI-C interaction with STAT3 inhibitor PIAS3 in repression of alpha-subunit of epithelial Na+ channel (alpha-ENaC) transcription by Ras activation in salivary epithelial cells". The Journal of Biological Chemistry. 276 (32): 29805–14. PMID 11390395.
- Röijer E, Nordkvist A, Ström AK, Ryd W, Behrendt M, Bullerdiek J, et al. (February 2002). "Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma". The American Journal of Pathology. 160 (2): 433–40. PMID 11839563.
External links
- HMGA2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Ellensburg 13-year-old grapples with life at 7 feet 3 inches tall: [1]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.