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HMGA2

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Template:PBB High mobility group AT-hook 2, also known as HMGA2, is a protein which in humans is encoded by the HMGA2 gene.[1][2][3]

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 enhancesome. 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.[3]

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 only expressed in humans during early development, and is reduced to undetectable or nearly undetectable levels of transcription in adult tissues.[4] The microRNA let-7 is largely responsible for this time-dependent regulation of HMGA2.[5] 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),[6] and genome-wide association studies linking HMGA2-associated SNPs to variation in human height.[7]

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).[8] 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.[5]

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.[9][10] The same mutations that lead to pituitary adenomas in mice can be found in similar cancers in humans.[9] Its presence is associated with poor prognosis for the patient, but also with sensitization of the cancer cells to certain forms of cancer therapy.[11] Specifically, 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.[11] 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.[11]

Characteristic mutations in HMGA2-high cancers

A very common finding in HMGA2-high cancers is the under-expression of let-7.[12] 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 (shortened). Specifically, the transcript is 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.[8]

Interactions

HMGA2 has been shown to interact with PIAS3[13] and NFKB1.[14]

The transport of HMGA2 to the nucleus is mediated by an interaction between its second AT-hook and importin-α2.[6]

See also

References

  1. ^ Ashar HR, Cherath L, Przybysz KM, Chada K (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ 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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b "Entrez Gene: HMGA2 high mobility group AT-hook 2".
  4. ^ 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 (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b Dröge P, Davey CA (2008). "Do cells let-7 determine stemness?". Cell Stem Cell. 2 (1): 8–9. doi:10.1016/j.stem.2007.12.003. PMID 18371414. {{cite journal}}: Unknown parameter |month= ignored (help)
  6. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ 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.
  8. ^ a b Mayr C, Hemann MT, Bartel DP (2007). "Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation". Science (journal). 315 (5818): 1576–9. doi:10.1126/science.1137999. PMC 2556962. PMID 17322030. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ a b Fedele M, Pierantoni GM, Visone R, Fusco A (2006). "Critical role of the HMGA2 gene in pituitary adenomas". Cell Cycle. 5 (18): 2045–8. PMID 16969098. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, Vollmer E, Bullerdiek J (2007). "HMGA2 overexpression in non-small cell lung cancer". Mol. Carcinog. 46 (7): 503–11. doi:10.1002/mc.20235. PMID 17477356. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b c Boo LM, Lin HH, Chung V, Zhou B, Louie SG, O'Reilly MA, Yen Y, Ann DK (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Shell S, Park SM, Radjabi AR, Schickel R, Kistner EO, Jewell DA, Feig C, Lengyel E, Peter ME (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Zentner, M D (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). United States: 29805–14. doi:10.1074/jbc.M103153200. ISSN 0021-9258. PMID 11390395. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link) CS1 maint: year (link)
  14. ^ Noro, Barbara (2003). "Molecular dissection of the architectural transcription factor HMGA2". Biochemistry. 42 (15). United States: 4569–77. doi:10.1021/bi026605k. ISSN 0006-2960. PMID 12693954. {{cite journal}}: Check date values in: |year= (help); Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: year (link)

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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