Steeper, Kate, 2010-2011

Kate Steeper
Kate
Steeper

Host research mentor: Thomas A. Rando, M.D, PhD, Department of Neurology and Neurological Sciences, Stanford University School of Medicine

Quiescent satellite cells (SCs) display heterogeneous expression of Pax3 which has been shown to play a role in proliferation and myogenic determination. p53 is known to be involved in the regulation of quiescence, self-renewal, cell fate, and cellular senescence. SCs from the diaphragm lose their myogenic fate at a much higher rate than SCs from the hindlimb. Early results show that p53 displays differential activity in the diaphragm versus the limb SCs. Indeed, when Pax3 is overexpressed in C2C12 cells p53 is destabilized. In addition, overexpression of Pax3 in C2C12 cells treated with an inhibitor of the proteasome, MG132, show an increase of p53 polyubiquitination, suggesting that overexpression of Pax3 induces proteasomal degradation of p53. Furthermore, p53 knock-down in hindlimb SCs increased fibrogenic conversion while Pax3 knock-down in diaphragm SCs increased the myogenic cell fate choice.

Our findings suggest that Pax3 and p53 degradation pathway mayinterfere with each other and may explain the differential fibrogenic conversion observed in the diaphragm versus the limb of patients with Duchenne muscular dystrophy (DMD) and in old mdx mice, the mouse model used for DMD.