A new role for the oncogenic high-mobility group A2 transcription factor in myogenesis of embryonic stem cells

• Published in: Oncogene Vol. 24; no. 41; pp. 6281 - 6291
• Main Authors: CARON, Leslie, BOST, Frédéric, PROT, Matthieu, HOFMAN, Paul, BINETRUY, Bernard
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 15-09-2005; Nature Publishing Group
• Subjects: Animals; Base Sequence; Biological and medical sciences; Body fat; Cardiomyocytes; Cell differentiation; Cell Differentiation - physiology; Cell lines; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells, Cultured; DNA Primers; Embryo cells; Embryo, Mammalian - cytology; Embryogenesis; Enzyme inhibitors; Fundamental and applied biological sciences. Psychology; High mobility group proteins; HMGA2 Protein - physiology; Kinases; Lymphocytes T; Mice; Mobility; Molecular and cellular biology; Muscle contraction; Muscle Fibers, Skeletal - cytology; Musculoskeletal system; MyoD protein; Myogenesis; Myogenin; Myosin; Myotubes; Oncogenes; Rapamycin; Skeletal muscle; Stem cell transplantation; Stem cells; Stem Cells - cytology; Teratocarcinoma - pathology; TOR protein; Transcription factors; Tumors; Stem cell; Mobility; ES cells; Transcription factor; HMGA2 transcription factor; Carcinogenesis; Myogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208781

The high mobility group type A-2 (HMGA 2) transcription factor is involved in proliferation and differentiation, mainly during embryogenesis. Its activated form (HMGA 2/T) presents oncogenic activities both in vivo and in vitro. However, its precise role during embryogenesis is unknown. We investigated its role during the commitment of mouse embryonic stem (ES) cells by constructing cell lines expressing either wild type (wt) or HMGA 2/T forms of the gene. Following differentiation, control and wt HMGA 2 ES cells did not display myotubes; whereas HMGA 2/T ES cell lines massively formed contractile myotubes. Furthermore, as opposed to control cells, HMGA 2/T ES cells highly expressed the muscle myosin heavy chain (MHC) marker. Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA 2/T cells. By contrast, commitment into adipocyte, neuron, and cardiomyocyte lineages was not affected. Teratocarcinomas induced by HMGA 2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA 2 or control tumours. Finally, rapamycin, an inhibitor of the mTOR kinase, downregulated endogenous HMGA-2 expression and inhibited myogenesis. This effect was prevented by overexpression of exogenous HMGA-2. Our results reveal a novel function of HMGA-2 in skeletal muscle differentiation.