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.
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 (Mus musculus).
HMGA2 contains three basic DNA-binding domains (AT-hooks) that cause the protein to bind to adenine-thymine (AT)-rich regions of nuclear DNA. HMGA2 does not directly promote or inhibit the transcription of any genes, but alters the structure of DNA and promotes the assembly of protein complexes that do regulate the transcription of genes. With few exceptions, HMGA2 is expressed in humans only during early development, and is reduced to undetectable or nearly undetectable levels of transcription in adult tissues. The microRNA let-7 is largely responsible for this time-dependent regulation of HMGA2. The apparent function of HMGA2 in proliferation and differentiation of cells during development is supported by the observation that mice with mutant HMGA2 genes are unusually small (pygmy phenotype), and genome-wide association studies linking HMGA2-associated SNPs to variation in human height.
Regulation by let-7
Let-7 inhibits production of specific proteins by complementary binding to their mRNA transcripts. The HMGA2 mature mRNA transcript contains seven regions complementary or nearly complementary to let-7 in its 3' untranslated region (UTR). Let-7 expression is very low during early human development, which coincides with the greatest transcription of HMGA2. The time-dependent drop in HMGA2 expression is caused by a rise in let-7 expression.
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. The same mutations that lead to pituitary adenomas in mice can be found in similar cancers in humans. Its presence is associated with poor prognosis for the patient, but also with sensitization of the cancer cells to certain forms of cancer therapy. To be specific, HMGA2-high cancers display an abnormally strong response to double strand breaks in DNA caused by radiation therapy and some forms of chemotherapy. Artificial addition of HMGA2 to some forms of cancer unresponsive to DNA damage cause them to respond to the treatment instead, although the mechanism by which this phenomenon occurs is also not understood. However, the expression of HMGA2 is also associated with increased rates of metastasis in breast cancer, and both metastasis and recurrence of squamous cell carcinoma. These properties are responsible for patients' poor prognoses. As with HMGA2's effects on the response to radiation and chemotherapy, the mechanism by which HMGA2 exerts these effects is unknown.
Characteristic mutations in HMGA2-high cancers
A very common finding in HMGA2-high cancers is the under-expression of let-7. 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.
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. (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., 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. ERCC1 protein expression was also reduced in a diet-related mouse model of colon cancer. 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).
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. 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
Li et al. showed that 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.
Base excision repair pathway
Summer et al. found that HGMA2 protein can efficiently 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. They demonstrated an interaction between human AP endonuclease 1 and HMGA2 in cancer cells, 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.
The transport of HMGA2 to the nucleus is mediated by an interaction between its second AT-hook and importin-α2.
- "Diseases that are genetically associated with HMGA2 view/edit references on wikidata".
- "Human PubMed Reference:".
- 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. doi:10.1006/geno.1996.0033. 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". Hum. Genet. 99 (1): 103–5. doi:10.1007/s004390050320. PMID 9003504.
- "Entrez Gene: HMGA2 high mobility group AT-hook 2".
- Fedele M, Battista S, Kenyon L, Baldassarre G, Fidanza V, Klein-Szanto AJ, Parlow AF, Visone R, Pierantoni GM, Outwater E, Santoro M, Croce CM, Fusco A (May 2002). "Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas". Oncogene. 21 (20): 3190–8. doi:10.1038/sj.onc.1205428. PMID 12082634.
- Dröge P, Davey CA (January 2008). "Do cells let-7 determine stemness?". Cell Stem Cell. 2 (1): 8–9. doi:10.1016/j.stem.2007.12.003. PMID 18371414.
- Cattaruzzi G, Altamura S, Tessari MA, Rustighi A, Giancotti V, Pucillo C, Manfioletti G (2007). "The second AT-hook of the architectural transcription factor HMGA2 is determinant for nuclear localization and function". Nucleic Acids Res. 35 (6): 1751–60. doi:10.1093/nar/gkl1106. PMC 1874589. PMID 17324944.
- Hammond SM, Sharpless NE (2008). "HMGA2, microRNAs, and stem cell aging". Cell. 135 (6): 1013–1016. doi:10.1016/j.cell.2008.11.026. PMID 19070572.
- Mayr C, Hemann MT, Bartel DP (March 2007). "Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation". Science. 315 (5818): 1576–9. doi:10.1126/science.1137999. PMC 2556962. PMID 17322030.
- Fedele M, Pierantoni GM, Visone R, Fusco A (September 2006). "Critical role of the HMGA2 gene in pituitary adenomas". Cell Cycle. 5 (18): 2045–8. doi:10.4161/cc.5.18.3211. PMID 16969098.
- Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, Vollmer E, Bullerdiek J (July 2007). "HMGA2 overexpression in non-small cell lung cancer". Mol. Carcinog. 46 (7): 503–11. doi:10.1002/mc.20235. PMID 17477356.
- Boo LM, Lin HH, Chung V, Zhou B, Louie SG, O'Reilly MA, Yen Y, Ann DK (August 2005). "High mobility group A2 potentiates genotoxic stress in part through the modulation of basal and DNA damage-dependent phosphatidylinositol 3-kinase-related protein kinase activation". Cancer Res. 65 (15): 6622–30. doi:10.1158/0008-5472.CAN-05-0086. PMID 16061642.
- Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, Feig C, Lengyel E, Peter ME (July 2007). "Let-7 expression defines two differentiation stages of cancer". Proc. Natl. Acad. Sci. U.S.A. 104 (27): 11400–5. doi:10.1073/pnas.0704372104. PMC 2040910. PMID 17600087.
- Motoyama K, Inoue H, Nakamura Y, Uetake H, Sugihara K, Mori M (Apr 2008). "Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family". Clinical Cancer Research. 14 (8): 2334–40. doi:10.1158/1078-0432.CCR-07-4667. PMID 18413822.
- Borrmann L, Schwanbeck R, Heyduk T, Seebeck B, Rogalla P, Bullerdiek J, Wisniewski JR (Dec 2003). "High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity". Nucleic Acids Research. 31 (23): 6841–51. doi:10.1093/nar/gkg884. PMC 290254. PMID 14627817.
- Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C (2012). "Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer". Genome Integr. 3 (1): 3. doi:10.1186/2041-9414-3-3. PMC 3351028. PMID 22494821.
- Smith DH, Fiehn AM, Fogh L, Christensen IJ, Hansen TP, Stenvang J, Nielsen HJ, Nielsen KV, Hasselby JP, Brünner N, Jensen SS (2014). "Measuring ERCC1 protein expression in cancer specimens: validation of a novel antibody". Scientific Reports. 4: 4313. doi:10.1038/srep04313. PMC 3945488. PMID 24603753.
- Prasad AR, Prasad S, Nguyen H, Facista A, Lewis C, Zaitlin B, Bernstein H, Bernstein C (2014). "Novel diet-related mouse model of colon cancer parallels human colon cancer". World J Gastrointest Oncol. 6 (7): 225–43. doi:10.4251/wjgo.v6.i7.225. PMC 4092339. PMID 25024814.
- Zha L, Wang Z, Tang W, Zhang N, Liao G, Huang Z (2012). "Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells". Mol. Cell. Biochem. 364 (1-2): 243–51. doi:10.1007/s11010-012-1224-z. PMID 22246783.
- Li AY, Boo LM, Wang SY, Lin HH, Wang CC, Yen Y, Chen BP, Chen DJ, Ann DK (2009). "Suppression of nonhomologous end joining repair by overexpression of HMGA2". Cancer Res. 69 (14): 5699–706. doi:10.1158/0008-5472.CAN-08-4833. PMC 2737594. PMID 19549901.
- Summer H, Li O, Bao Q, Zhan L, Peter S, Sathiyanathan P, Henderson D, Klonisch T, Goodman SD, Dröge P (2009). "HMGA2 exhibits dRP/AP site cleavage activity and protects cancer cells from DNA-damage-induced cytotoxicity during chemotherapy". Nucleic Acids Res. 37 (13): 4371–84. doi:10.1093/nar/gkp375. PMC 2715238. PMID 19465398.
- Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK (Aug 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". J. Biol. Chem. 276 (32): 29805–14. doi:10.1074/jbc.M103153200. PMID 11390395.
- Noro B, Licheri B, Sgarra R, Rustighi A, Tessari MA, Chau KY, Ono SJ, Giancotti V, Manfioletti G (Apr 2003). "Molecular dissection of the architectural transcription factor HMGA2". Biochemistry. 42 (15): 4569–77. doi:10.1021/bi026605k. PMID 12693954.
- Pedeutour F, Ligon AH, Morton CC (1999). "[Genetics of uterine leiomyomata]". Bulletin du cancer. 86 (11): 920–8. PMID 10586108.
- Reeves R, Beckerbauer L (2001). "HMGI/Y proteins: flexible regulators of transcription and chromatin structure.". Biochim. Biophys. Acta. 1519 (1–2): 13–29. doi:10.1016/S0167-4781(01)00215-9. PMID 11406267.
- Manfioletti G, Giancotti V, Bandiera A, Buratti E, Sautière P, Cary P, Crane-Robinson C, Coles B, Goodwin GH (1992). "cDNA cloning of the HMGI-C phosphoprotein, a nuclear protein associated with neoplastic and undifferentiated phenotypes". Nucleic Acids Res. 19 (24): 6793–7. doi:10.1093/nar/19.24.6793. PMC 329311. PMID 1762909.
- Chau KY, Patel UA, Lee KL, Lam HY, Crane-Robinson C (1996). "The gene for the human architectural transcription factor HMGI-C consists of five exons each coding for a distinct functional element". Nucleic Acids Res. 23 (21): 4262–6. doi:10.1093/nar/23.21.4262. PMC 307378. PMID 7501444.
- Schoenmakers EF, Mols R, Wanschura S, Kools PF, Geurts JM, Bartnitzke S, Bullerdiek J, van den Berghe H, Van de Ven WJ (1995). "Identification, molecular cloning, and characterization of the chromosome 12 breakpoint cluster region of uterine leiomyomas". Genes Chromosomes Cancer. 11 (2): 106–18. doi:10.1002/gcc.2870110207. PMID 7529547.
- Ashar HR, Fejzo MS, Tkachenko A, Zhou X, Fletcher JA, Weremowicz S, Morton CC, Chada K (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. doi:10.1016/0092-8674(95)90052-7. PMID 7606786.
- Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJ (1995). "Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours". Nat. Genet. 10 (4): 436–44. doi:10.1038/ng0895-436. PMID 7670494.
- Patel UA, Bandiera A, Manfioletti G, Giancotti V, Chau KY, Crane-Robinson C (1994). "Expression and cDNA cloning of human HMGI-C phosphoprotein". Biochem. Biophys. Res. Commun. 201 (1): 63–70. doi:10.1006/bbrc.1994.1669. PMID 8198613.
- Ashar HR, Cherath L, Przybysz KM, Chada K (1997). "Genomic characterization of human HMGIC, a member of the accessory transcription factor family found at translocation breakpoints in lipomas". Genomics. 31 (2): 207–14. doi:10.1006/geno.1996.0033. PMID 8824803.
- Ishwad CS, Shriver MD, Lassige DM, Ferrell RE (1997). "The high mobility group I-C gene (HMGI-C): polymorphism and genetic localization". Hum. Genet. 99 (1): 103–5. doi:10.1007/s004390050320. PMID 9003504.
- Petit MM, Swarts S, Bridge JA, Van de Ven WJ (1998). "Expression of reciprocal fusion transcripts of the HMGIC and LPP genes in parosteal lipoma". Cancer Genet. Cytogenet. 106 (1): 18–23. doi:10.1016/S0165-4608(98)00038-7. PMID 9772904.
- Schoenmakers EF, Huysmans C, Van de Ven WJ (1999). "Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas". Cancer Res. 59 (1): 19–23. PMID 9892177.
- Gattas GJ, Quade BJ, Nowak RA, Morton CC (1999). "HMGIC expression in human adult and fetal tissues and in uterine leiomyomata". Genes Chromosomes Cancer. 25 (4): 316–22. doi:10.1002/(SICI)1098-2264(199908)25:4<316::AID-GCC2>3.0.CO;2-0. PMID 10398424.
- Schwanbeck R, Manfioletti G, Wiśniewski JR (2000). "Architecture of high mobility group protein I-C.DNA complex and its perturbation upon phosphorylation by Cdc2 kinase". J. Biol. Chem. 275 (3): 1793–801. doi:10.1074/jbc.275.3.1793. PMID 10636877.
- Piekielko A, Drung A, Rogalla P, Schwanbeck R, Heyduk T, Gerharz M, Bullerdiek J, Wiśniewski JR (2001). "Distinct organization of DNA complexes of various HMGI/Y family proteins and their modulation upon mitotic phosphorylation". J. Biol. Chem. 276 (3): 1984–92. doi:10.1074/jbc.M004065200. PMID 11034995.
- Rogalla P, Lemke I, Kazmierczak B, Bullerdiek J (2001). "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. doi:10.1002/1098-2264(2000)9999:9999<1::AID-GCC1043>3.0.CO;2-N. PMID 11066083.
- Zentner MD, Lin HH, Deng HT, Kim KJ, Shih HM, Ann DK (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". J. Biol. Chem. 276 (32): 29805–14. doi:10.1074/jbc.M103153200. PMID 11390395.
- Röijer E, Nordkvist A, Ström AK, Ryd W, Behrendt M, Bullerdiek J, Mark J, Stenman G (2002). "Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma". Am. J. Pathol. 160 (2): 433–40. doi:10.1016/S0002-9440(10)64862-6. PMC 1850659. PMID 11839563.
- HMGA2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Ellensburg 13-year-old grapples with life at 7 feet 3 inches tall: