Transgenic Mice Expressing a Truncated Form of the High Mobility Group I-C Protein Develop Adiposity and an Abnormally High Prevalence of Lipomas

Arlotta, Paola; Tai, Albert; Manfioletti, Guidalberto; Clifford, Charles B.; Jay, Gregory D.; Ono, Santa Jeremy

doi:10.1074/jbc.m000564200

Cited by 138 publications

(111 citation statements)

References 43 publications

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“…HMGA2 is certainly the important gene of this rearrangement in lipomas 3,4 as there are no fewer than 41 other chromosomal loci as partners of HMGA2. 3,30,31 However, conventional lipomas with normal karyotypes 31 or with aberrations in 6p21 or on chromosome 13q have been reported. These data could explain that in our series, roughly 14% of conventional lipomas do not express HMGA2.…”

Section: Discussionmentioning

confidence: 99%

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

et al. 2010

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The high mobility group A (HMGA2) gene encodes a protein that alters chromatin structure and regulates the transcription of many genes; it is implicated in both benign and malignant neoplasias, but its rearrangements are a feature of development of several mesenchymal tumors. Given its implication in these tumors and particularly adipocytic tumors, and the availability of antibodies usable on paraffin-embedded tissues, we evaluated the immunohistochemical expression of this gene in a series of 1052 mesenchymal tumors. The objective was to define the value and limitations of HMGA2 immunohistochemical expression for histotyping, and compare with molecular data reported in the literature. We thus analyzed 880 cases on tissue microarray and 182 cases on whole sections (211 adipocytic tumors, 628 sarcomas, 213 benign mesenchymal tumors, and 10 normal adipose tissues). A nuclear immunostaining was detected in 86% of conventional and intramuscular lipomas, in 86% of well-differentiated liposarcomas and in 67% of dedifferentiated liposarcomas, as opposed to 16% of other benign adipose tumors and to 15% of non-well-differentiated liposarcoma/dedifferentiated liposarcoma sarcomas. Among benign mesenchymal tumors and lesions, it was detected in 90% of nodular fasciitis and in 88% of benign fibrous histiocytomas with respective specificities of 85 and 100%, and in 90% of aggressive angiomyxoma, contrary to other vulvovaginal tumor types, which expressed HMGA2 only rarely. The normal adipose tissue was always negative for HMGA2. Although not specific, immunohistochemical detection of the HMGA2 protein is helpful for the distinction of normal adipose tissue from well-differentiated lesions, particularly on biopsy or on re-excision. It is less sensitive than MDM2/CDK4 for dedifferentiated liposarcomas diagnosis, but it appears more specific to distinguish dedifferentiated liposarcomas from other poorly differentiated sarcomas. Finally, and may be more importantly, HMGA2 is useful for the diagnosis of benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors.

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Section: Discussionmentioning

confidence: 99%

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

et al. 2010

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“…Such a HMGA2Tr induces neoplastic transformation of NIH/3T3 murine fibroblasts [35]. Transgenic mice aberrantly expressing this truncated HMGA2 protein present gigantism that is associated with lipomatosis [36], develop adiposity, and display an abnormal high prevalence of lipomas [37]. To study the effect of HMGA2Tr on IMP2, NIH/3T3 cell lines overexpressing HMGA2 or HMGA2Tr were made by retroviral transduction.…”

Section: Imp2 Is a Downstream Target Of Hmga2mentioning

confidence: 99%

Differential regulation of the insulin‐like growth factor II mRNA‐binding protein genes by architectural transcription factor HMGA2

Brants

Ayoubi

Chada³

et al. 2004

FEBS Letters

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The developmentally regulated architectural transcription factor, high mobility group A2 (HMGA2), is involved in growth regulation and plays an important role in embryogenesis and tumorigenesis. Little is known, however, about its downstream targets. We performed a search for genes of which expression is strongly altered during embryonic development in two HMGA2-deficient mouse strains, which display a pygmyphenotype, as compared to wild-type mice. We found that the insulin-like growth factor II mRNA-binding protein 2 gene (IMP2), but not its family members IMP1 and IMP3, was robustly downregulated in mutant E12.5 embryos. Furthermore, we show that wild-type HMGA2 and its tumor-specific truncated form have opposite effects on IMP2 expression. Our results clearly indicate that HMGA2 differentially regulates expression of IMP family members during embryogenesis.

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“…The truncation of HMGA2, rather than its fusion with other genes, has also been shown to be responsible for cell transformation . This was confirmed in transgenic mice carrying a truncated HMGA2, which developed a giant phenotype together with a marked expansion of the retroperitoneal and subcutaneous white adipose tissues (Battista et al, 1999;Arlotta et al, 2000). Interestingly, most of these tumours related to the alteration in HMGA2 are of nonepithelial origin.…”

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confidence: 93%

An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue

et al. 2003

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The altered form of the high-mobility group A2 (HMGA2) gene is somehow related to the generation of human benign and malignant tumours of mesenchymal origin. However, only a few data on the expression of HMGA2 in malignant tumour originating from epithelial tissue are available. In this study, we examined the HMGA2 expression level in pancreatic carcinoma, and investigated whether alterations in the HMGA2 expression level are associated with a malignant phenotype in pancreatic tissue. High-mobility group A2 mRNA and protein expression was determined in eight surgically resected specimens of non-neoplastic tissue (six specimens of normal pancreatic tissue and two of chronic pancreatitis tissue) and 27 pancreatic carcinomas by highly sensitive reverse transcriptase -polymerase chain reaction (RT -PCR) techniques and immunohistochemical staining, respectively. Reverse transcriptase -polymerase chain reaction analysis revealed the expression of the HMGA2 gene in non-neoplastic pancreatic tissue, although its expression level was significantly lower than that in carcinoma. Immunohistochemical analysis indicated that the presence of the HMGA2 gene in non-neoplastic pancreatic tissue observed in RT -PCR reflects its abundant expression in islet cells, together with its focal expression in duct epithelial cells. Intense and multifocal or diffuse HMGA2 immunoreactivity was noted in all the pancreatic carcinoma examined. A strong correlation between HMGA2 overexpression and the diagnosis of carcinoma was statistically verified. Based on these findings, we propose that an increased expression level of the HMGA2 protein is closely associated with the malignant phenotype in the pancreatic exocrine system, and accordingly, HMGA2 could serve as a potential diagnostic molecular marker for distinguishing pancreatic malignant cells from non-neoplastic pancreatic exocrine cells.

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Transgenic Mice Expressing a Truncated Form of the High Mobility Group I-C Protein Develop Adiposity and an Abnormally High Prevalence of Lipomas

Cited by 138 publications

References 43 publications

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

Differential regulation of the insulin‐like growth factor II mRNA‐binding protein genes by architectural transcription factor HMGA2

An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue

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