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Derepression of HMGA2 gene expression in retinoblastoma is associated with cell proliferation

Chau, KY; Manfioletti, G; Cheung-Chau, KW; Fusco, A; Dhomen, N; Sowden, JC; Sasabe, T; ... Ono, SJ; + view all (2003) Derepression of HMGA2 gene expression in retinoblastoma is associated with cell proliferation. MOL MED , 9 (5-8) 154 - 165. Gold open access

Abstract

To assess whether retinoblastoma formation is associated with the expression of high mobility group (HMG) A2 protein, a transcription factor that is highly expressed during embryogenesis and completely repressed in normal adult tissues, we performed Northern and Western blots and RT-PCR analyses, and immunohistochemistry to test for HMGA2 expression. We used established retinoblastoma cell lines in tumors grown in nude mice and clinical retinoblastoma specimens, and contrasted these tumors with normal embryonic and adult retina. Adenoviral-mediated antisense experiments were conducted on the retinoblastoma cell lines to suppress HMGA2 expression and determine if cell proliferation is HMGA2dependent. We also transfected a retinoblastoma cell line to identify cis-regulatory elements and transcription initiation sites on the HMGA2 gene promoter. HMGA2 gene expression was silenced in terminally differentiated retina of 6-wk-old mice, but it was detected in retina of a 13.5-d postcoitum embryo. Reactivation of HMGA2 gene expression was observed in the retinoblastoma cell lines Y79, WERI-Rb1, and TOTL-1, in tumors derived from some of these cells propagated in nude mice, and in a high frequency of retinoblastomas excised from human patients. This suggests that expression of HMGA2 gene in retinoblastoma cells involves a derepression process. By using an antisense approach to block HMGA2 expression, we observed a decrease in the number of proliferating retinoblastoma cells. As a 1 st step toward understanding HMGA2 gene reactivation in retinoblastoma, we mapped the 2 transcription initiation sites and associated positive regulatory elements within the WERI-Rb1 cells. Our discovery of derepression of HMGA2 gene expression in retinoblastoma provides the 1 st evidence that this protein might contribute to neoplastic transformation of retina cells.

Type: Article
Title: Derepression of HMGA2 gene expression in retinoblastoma is associated with cell proliferation
Open access status: An open access publication
Publisher version: http://www.molmed.org/
Keywords: ARCHITECTURAL TRANSCRIPTION FACTOR, MOBILITY GROUP PROTEIN, I-C PROTEIN, NEOPLASTIC TRANSFORMATION, MESENCHYMAL TUMORS, GENOMIC STRUCTURE, THYROID-CELLS, CDNA CLONING, DNA, SEQUENCE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Development Bio and Cancer Prog
URI: http://discovery.ucl.ac.uk/id/eprint/176986
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