Genomes and Genes
Summary: An 11-kDa AT-hook motif-containing (AT-HOOK MOTIFS) protein that binds to the minor grove of AT-rich regions of DNA. It is the full-length product of the alternatively-spliced HMGA1 gene and may function as an architectural chromatin binding protein that is involved in transcriptional regulation.
- Trapasso F, Sarti M, Cesari R, Yendamuri S, Dumon K, Aqeilan R, et al. Therapy of human pancreatic carcinoma based on suppression of HMGA1 protein synthesis in preclinical models. Cancer Gene Ther. 2004;11:633-41 pubmed..Therefore, suppression of HMGA1 protein synthesis by an HMGA1 antisense approach seems to be a feasible treatment strategy in pancreatic carcinomas. ..
- Manabe T, Katayama T, Tohyama M. HMGA1a recognition candidate DNA sequences in humans. PLoS ONE. 2009;4:e8004 pubmed publisher..The candidate sequences presented here represent important information for research into the various roles of HMGA1a, including cell differentiation, death, growth, proliferation, and the pathogenesis of cancer. ..
- Pierantoni G, Battista S, Pentimalli F, Fedele M, Visone R, Federico A, et al. A truncated HMGA1 gene induces proliferation of the 3T3-L1 pre-adipocytic cells: a model of human lipomas. Carcinogenesis. 2003;24:1861-9 pubmed..These results suggest a critical role played by HMGA1 rearrangements in the generation of human lipomas. ..
- Lin S. Identification of an NF-Y/HMG-I(Y)-binding site in the human IL-10 promoter. Mol Immunol. 2006;43:1325-31 pubmed..These findings suggest that NF-Y and HMG-I(Y) may play an important role in regulating the IL-10 promoter activity in B cells. ..
- Di Cello F, Hillion J, Kowalski J, Ronnett B, Aderinto A, Huso D, et al. Cyclooxygenase inhibitors block uterine tumorigenesis in HMGA1a transgenic mice and human xenografts. Mol Cancer Ther. 2008;7:2090-5 pubmed publisher..Importantly, these drugs have lower toxicity than chemotherapeutic agents used to treat advanced-stage uterine cancers. ..
- Thomae A, Pich D, Brocher J, Spindler M, Berens C, Hock R, et al. Interaction between HMGA1a and the origin recognition complex creates site-specific replication origins. Proc Natl Acad Sci U S A. 2008;105:1692-7 pubmed publisher..Our experiments indicate that chromatin proteins can target ORC to DNA, suggesting they might specify origins of DNA replication in metazoan cells. ..
- Adair J, Maloney S, Dement G, Wertzler K, Smerdon M, Reeves R. High-mobility group A1 proteins inhibit expression of nucleotide excision repair factor xeroderma pigmentosum group A. Cancer Res. 2007;67:6044-52 pubmed
- Duncan B, Zhao K. HMGA1 mediates the activation of the CRYAB promoter by BRG1. DNA Cell Biol. 2007;26:745-52 pubmed..Our data indicate that HMGA1 nonhistone chromatin proteins, the SWI/SNF chromatin remodeling complexes, and sequence-specific transcription factors act together to regulate the expression of the CRYAB gene. ..
- Pedulla M, Treff N, Resar L, Reeves R. Sequence and analysis of the murine Hmgiy (Hmga1) gene locus. Gene. 2001;271:51-8 pubmed
- Manabe T, Katayama T, Sato N, Gomi F, Hitomi J, Yanagita T, et al. Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease. Cell Death Differ. 2003;10:698-708 pubmed..HMGA1a levels were significantly increased in the brain tissue from sporadic AD patients. We propose a novel mechanism of sporadic AD that involves HMGA1a-induced aberrant splicing of PS2 pre-mRNA in the absence of any mutations. ..
- Wei J, Wu X, Peng Y, Shi G, Basturk O, Olca B, et al. Regulation of HMGA1 expression by microRNA-296 affects prostate cancer growth and invasion. Clin Cancer Res. 2011;17:1297-305 pubmed publisher..Our results indicate that miR-296 regulates HMGA1 expression and is associated with PC growth and invasion. ..
- Takaha N, Resar L, Vindivich D, Coffey D. High mobility group protein HMGI(Y) enhances tumor cell growth, invasion, and matrix metalloproteinase-2 expression in prostate cancer cells. Prostate. 2004;60:160-7 pubmed..Overexpression of HMG-I in prostate cancer cells enhances cell growth, invasion, and expression of the proform of MMP-2, which may initiate early steps involved in the metastatic cascade. ..
- Murua Escobar H, Soller J, Richter A, Meyer B, Winkler S, Bullerdiek J, et al. "Best friends" sharing the HMGA1 gene: comparison of the human and canine HMGA1 to orthologous other species. J Hered. 2005;96:777-81 pubmed..Additionally, we compared the known human, canine, murine, rat, hamster, bovine, pig, Xenopus, and chicken HMGA1 transcripts. ..
- Ueda Y, Watanabe S, Tei S, Saitoh N, Kuratsu J, Nakao M. High mobility group protein HMGA1 inhibits retinoblastoma protein-mediated cellular G0 arrest. Cancer Sci. 2007;98:1893-901 pubmed..Our present findings indicate that overexpression of HMGA1 disturbs RB-mediated cell arrest, suggesting a negative control of RB by HMGA1. ..
- Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F, et al. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nat Med. 2005;11:765-73 pubmed
- Flohr A, Rogalla P, Bonk U, Puettmann B, Buerger H, Gohla G, et al. High mobility group protein HMGA1 expression in breast cancer reveals a positive correlation with tumour grade. Histol Histopathol. 2003;18:999-1004 pubmed publisher..Statistical analysis revealed a strong correlation between tumour grade and HMGA1 expression (rs=0.3516, p<0.0001). Thus, the HMGA1 expression level can be considered a potential prognostic marker for breast cancer. ..
- Chiappetta G, Botti G, Monaco M, Pasquinelli R, Pentimalli F, Di Bonito M, et al. HMGA1 protein overexpression in human breast carcinomas: correlation with ErbB2 expression. Clin Cancer Res. 2004;10:7637-44 pubmed..36; P=0.065). Taken together, these results suggest that HMGA1 expression might be a novel indicator for the diagnosis and prognosis of human breast cancer. ..
- Hommura F, Katabami M, Leaner V, Donninger H, Sumter T, Resar L, et al. HMG-I/Y is a c-Jun/activator protein-1 target gene and is necessary for c-Jun-induced anchorage-independent growth in Rat1a cells. Mol Cancer Res. 2004;2:305-14 pubmed..Taken together, these results suggest that HMG-I/Y is a direct transcriptional target of c-Jun necessary for c-Jun-induced anchorage-independent growth in Rat1a cells. ..
- Resar L. The high mobility group A1 gene: transforming inflammatory signals into cancer?. Cancer Res. 2010;70:436-9 pubmed publisher..Further elucidation of HMGA1 function in transformation promises to have a major impact on our war on cancer. ..
- Foti D, Iuliano R, Chiefari E, Brunetti A. A nucleoprotein complex containing Sp1, C/EBP beta, and HMGI-Y controls human insulin receptor gene transcription. Mol Cell Biol. 2003;23:2720-32 pubmed
- Sgarra R, Diana F, Bellarosa C, Dekleva V, Rustighi A, Toller M, et al. During apoptosis of tumor cells HMGA1a protein undergoes methylation: identification of the modification site by mass spectrometry. Biochemistry. 2003;42:3575-85 pubmed..In some tumor cells, HMGA1a protein is already methylated to an extent that depends on cell type...
- Eilebrecht S, Wilhelm E, Benecke B, Bell B, Benecke A. HMGA1 directly interacts with TAR to modulate basal and Tat-dependent HIV transcription. RNA Biol. 2013;10:436-44 pubmed publisher..Our results support a model in which the HMGA1/TAR interaction prevents the binding of transcription-activating cellular co-factors and Tat, subsequently leading to reduced HIV-1 transcription...
- Hillion J, Dhara S, Sumter T, Mukherjee M, Di Cello F, Belton A, et al. The high-mobility group A1a/signal transducer and activator of transcription-3 axis: an achilles heel for hematopoietic malignancies?. Cancer Res. 2008;68:10121-7 pubmed publisher..Our results show that the HMGA1a-STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a. ..
- Sarhadi V, Wikman H, Salmenkivi K, Kuosma E, Sioris T, Salo J, et al. Increased expression of high mobility group A proteins in lung cancer. J Pathol. 2006;209:206-12 pubmed..As HMGA proteins were expressed in about 90% of lung carcinomas and their expression was inversely associated with survival, they may provide useful markers for lung cancer diagnosis and prognosis. ..
- Eilebrecht S, Benecke B, Benecke A. 7SK snRNA-mediated, gene-specific cooperativity of HMGA1 and P-TEFb. RNA Biol. 2011;8:1084-93 pubmed publisher..7SK RNA thus establishes gene-dependent plasticity between HMGA1 chromatin remodeling and transcription initiation and P-TEFb transcription elongation. ..
- Takeuchi I, Takaha N, Nakamura T, Hongo F, Mikami K, Kamoi K, et al. High mobility group protein AT-hook 1 (HMGA1) is associated with the development of androgen independence in prostate cancer cells. Prostate. 2012;72:1124-32 pubmed publisher..These data suggest that elevated expression of HMGA1 is associated with the transition of PCa cells from androgen-sensitive to androgen-independent growth and plays a role in the cell growth of androgen-independent PCa cells. ..
- Liau S, Jazag A, Whang E. HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma. Cancer Res. 2006;66:11613-22 pubmed..Our findings suggest that HMGA1 may be a novel molecular determinant of invasiveness and metastasis, as well as a potential therapeutic target, in pancreatic adenocarcinoma. ..
- Zhang Q, Zhang K, Zou Y, Perna A, Wang Y. A quantitative study on the in vitro and in vivo acetylation of high mobility group A1 proteins. J Am Soc Mass Spectrom. 2007;18:1569-78 pubmed..Our results showed that all the above five lysine residues were also acetylated in vivo, with Lys-64, Lys-66 and Lys-70 in HMGA1a exhibiting higher levels of acetylation than Lys-14 and Lys-73. ..
- Reeves R, Edberg D, Li Y. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol. 2001;21:575-94 pubmed
- Himes S, Coles L, Reeves R, Shannon M. High mobility group protein I(Y) is required for function and for c-Rel binding to CD28 response elements within the GM-CSF and IL-2 promoters. Immunity. 1996;5:479-89 pubmed..Expression of HMG I or c-Rel antisense RNA inhibited CD28 activation of the IL-2 and GM-CSF promoters, implying that HMG I(Y) enhancement of c-Rel binding plays an important role in the activity of the CD28REs. ..
- Tallini G, Vanni R, Manfioletti G, Kazmierczak B, Faa G, Pauwels P, et al. HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes. Lab Invest. 2000;80:359-69 pubmed
- Kim H, Kelly J, Leonard W. The basis for IL-2-induced IL-2 receptor alpha chain gene regulation: importance of two widely separated IL-2 response elements. Immunity. 2001;15:159-72 pubmed..Thus, the IL-2 inducibility of the IL-2Ralpha gene is unexpectedly mediated by two widely separated regulatory Stat5-dependent elements, located both upstream and downstream of the transcription initiation sites. ..
- Dhar A, Hu J, Reeves R, Resar L, Colburn N. Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation. Oncogene. 2004;23:4466-76 pubmed
- Shah S, Resar L. High mobility group A1 and cancer: potential biomarker and therapeutic target. Histol Histopathol. 2012;27:567-79 pubmed publisher..We also review previous attempts to target HMGA1 pathways in cancer. Further study of HMGA1 promises to have a major impact on our ability to understand and treat cancer. ..
- Bonnefoy E, Bandu M, Doly J. Specific binding of high-mobility-group I (HMGI) protein and histone H1 to the upstream AT-rich region of the murine beta interferon promoter: HMGI protein acts as a potential antirepressor of the promoter. Mol Cell Biol. 1999;19:2803-16 pubmed..The displacement by HMGI protein of histone H1 could help to convert the IFN-beta promoter from a repressed to an active state. ..
- Palmieri D, D Angelo D, Valentino T, De Martino I, Ferraro A, Wierinckx A, et al. Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis. Oncogene. 2012;31:3857-65 pubmed publisher..Therefore, these results indicate that the downregulation of the miRNAs able to target the HMGA genes could contribute to increase HMGA protein levels in human pituitary adenomas, and then to pituitary tumorigenesis. ..
- Shah S, Kerr C, Cope L, Zambidis E, Liu C, Hillion J, et al. HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks. PLoS ONE. 2012;7:e48533 pubmed publisher..Although further studies are needed, these HMGA1 pathways could be exploited in regenerative medicine or as novel therapeutic targets for poorly differentiated, stem-like cancers. ..
- Aiello A, Pandini G, Sarfstein R, Werner H, Manfioletti G, Vigneri R, et al. HMGA1 protein is a positive regulator of the insulin-like growth factor-I receptor gene. Eur J Cancer. 2010;46:1919-26 pubmed publisher..Our data indicate, therefore, that HMGA1 protein is a positive regulator of IGF-IR expression and that HMGA1 overexpression may contribute to IGF-IR dysregulation in cancer cells. ..
- Esposito F, Tornincasa M, Chieffi P, De Martino I, Pierantoni G, Fusco A. High-mobility group A1 proteins regulate p53-mediated transcription of Bcl-2 gene. Cancer Res. 2010;70:5379-88 pubmed publisher..Therefore, this study suggests a novel mechanism, based on Bcl-2 induction, by which HMGA1 overexpression contributes to the escape from apoptosis leading to neoplastic transformation. ..
- Fedele M, Pentimalli F, Baldassarre G, Battista S, Klein Szanto A, Kenyon L, et al. Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene. 2005;24:3427-35 pubmed..Taken together, these data indicate an oncogenic role of the HMGA1 gene also in vivo. ..
- Chiefari E, Paonessa F, Iiritano S, Le Pera I, Palmieri D, Brunetti G, et al. The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis. BMC Biol. 2009;7:24 pubmed publisher..Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications. ..
- Reeves R, Leonard W, Nissen M. Binding of HMG-I(Y) imparts architectural specificity to a positioned nucleosome on the promoter of the human interleukin-2 receptor alpha gene. Mol Cell Biol. 2000;20:4666-79 pubmed..Together, these findings suggest a role for the HMG-I(Y) protein in assisting the remodeling of a critically positioned nucleosome on the PRRII promoter element during IL-2Ralpha transcriptional activation in lymphocytes in vivo. ..
- Paonessa F, Foti D, Costa V, Chiefari E, Brunetti G, Leone F, et al. Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer. Cancer Res. 2006;66:5085-93 pubmed..Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis. ..
- Marquez M, Huyvaert M, Perry J, Pearson R, Falchi M, Morris A, et al. Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. Diabetes. 2012;61:524-30 pubmed publisher..Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease. ..
- Schuldenfrei A, Belton A, Kowalski J, Talbot C, Di Cello F, Poh W, et al. HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis. BMC Genomics. 2011;12:549 pubmed publisher..These results provide insight into HMGA1 function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant HMGA1 expression. ..
- Friedmann M, Holth L, Zoghbi H, Reeves R. Organization, inducible-expression and chromosome localization of the human HMG-I(Y) nonhistone protein gene. Nucleic Acids Res. 1993;21:4259-67 pubmed..And, finally, we localized the gene to the short arm of chromosome 6 (6p) in a region that is known to be involved in rearrangements, translocations and other abnormalities correlated with a number of human cancers. ..
- Wood L, Mukherjee M, Dolde C, Xu Y, Maher J, Bunton T, et al. HMG-I/Y, a new c-Myc target gene and potential oncogene. Mol Cell Biol. 2000;20:5490-502 pubmed..These findings indicate that HMG-I/Y is a c-Myc target gene involved in neoplastic transformation and a member of a new class of potential oncogenes. ..
- Fedele M, Fidanza V, Battista S, Pentimalli F, Klein Szanto A, Visone R, et al. Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice. Cancer Res. 2006;66:2536-43 pubmed..Therefore, the data reported here indicate the critical role of HMGA1 in heart development and growth, and reveal an unsuspected antioncogenic potential for this gene in hematologic malignancies. ..
- Liu J, Schiltz J, Ashar H, Chada K. Hmga1 is required for normal sperm development. Mol Reprod Dev. 2003;66:81-9 pubmed..Our results suggest that both alleles of Hmga1 are required for normal sperm production in the mouse. ..
- Takaha N, Sowa Y, Takeuchi I, Hongo F, Kawauchi A, Miki T. Expression and role of HMGA1 in renal cell carcinoma. J Urol. 2012;187:2215-22 pubmed publisher..HMGA1 is a potential target for novel therapeutic modalities for metastatic renal cell carcinoma. ..
- Edberg D, Bruce J, Siems W, Reeves R. In vivo posttranslational modifications of the high mobility group A1a proteins in breast cancer cells of differing metastatic potential. Biochemistry. 2004;43:11500-15 pubmed..These findings suggest that examination of the PTM patterns on HMGA1 proteins may provide valuable information concerning the physiological and phenotypic state of mammalian cells. ..