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99 TESTOSTERONE MODULATES TRANSFORMING GROWTH FACTOR β SIGNALING PATHWAY GENES IN MESENCHYMAL PLURIPOTENT C3H 10T1/2 STEM CELLS: IMPLICATIONS IN REGULATION OF BODY COMPOSITION.
  1. R. Singh,
  2. M. Braga,
  3. J. N. Artaza,
  4. S. Bhasin,
  5. N. Gonzalez-Cadavid,
  6. R. Charles
  1. Drew University and RCMI Molecular Medicine and DNA Stem Cell Core, Los Angeles, CA

Abstract

Transforming growth factor β (TGFβ) family members play important roles in directing the fate of mesenchymal stem cells. We have previously demonstrated that testosterone promotes the commitment of pluripotent C3H 10T1/2 cells to promote myogenesis and inhibit adipogenesis via androgen receptor (AR)-dependent pathway. The objective of our current study is to identify possible target genes in TGF-β signaling pathway which may be regulated by androgens. Our microarray analysis in C3H 10T1/2 cells treated with or without testosterone (100 nM) for either 3 hours (early) or 4 days (late) suggest that T significantly up-regulates several genes, including FKBP1B, a regulator of type I receptor, follistatin (Fst, which binds and inhibits myostatin (Mst), a well-known inhibitor of muscle mass, Smad 7, BMP10, RunX1, GDF1, and GDF3, whereas it down-regulates Smad2/3 among other genes. In parallel studies we assessed the effects of T treatment on myostatin (a positive regulator of TGF-β, also termed GDF8) induced genes. Our data suggest that T up-regulates Fst, RunX1, Smad7, and several other genes in these cells pretreated with Mst. We confirmed these findings by real-time quantitative PCR analysis. Our immunocytochemical and Western blot analysis data suggest that testosterone inhibits Smad 2/3 phosphorylation induced by recombinant Mst and TGF-β and up-regulates Smad7, an inhibitory Smad in the TGF-β signaling pathway. Combined with our previous findings that T activates AR/β-catenin/TCF4 pathway to up-regulate Fst (Singh et al, 2005, Endocrinology), a known Wnt downstream target gene and inhibitor of TGF-β signaling, with a putative TCF4 binding site in the promoter region, our current data suggest that T may mediate its inhibitory action on the TGF-β pathway to regulate the fate of pluripotent stem cells. Our findings may provide a rationale for targeting key components of TGF-β family pathway genes that are responsible for regulating muscle, fat, and bone differentiation of pluripotent stem cells and thereby regulate body composition.

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