The dual effects of Cdh1/APC in myogenesis.

Ubiquitin-dependent proteolysis plays an important role in regulating fundamental biological functions, including cell division and cellular differentiation. Previous studies implicate the ubiquitin-proteasome system (UPS) in myogenic differentiation through regulating cell cycle progression and modulating myogenic factors such as MyoD and Myf5. Certain ubiquitin protein ligases, including the SCF complex and APC, have been suggested to govern terminal muscle differentiation. However, the underlying mechanism of regulation of both the cell cycle and myogenic factors by the UPS during this process remains unclear. We have dissected the role of the UPS in myogenic differentiation using an in vitro muscle differentiation system based on C2C12 cells. We demonstrate that Cdh1-APC regulates two critical proteins, Skp2 and Myf5, for proteolysis during muscle differentiation. The targeting of Skp2 by Cdh1-APC for destruction results in elevation of p21 and p27, which are crucial for coordinating cellular division and differentiation. Degradation of Myf5 by Cdh1-APC facilitates myogenic fusion. Knockdown of Cdh1 by siRNA significantly attenuates muscle differentiation. Taken together, Cdh1-APC is an important ubiquitin E3 ligase that modulates muscle differentiation through coordinating cell cycle progression and initiating the myogenic differentiation program.