Post-translational control of Myc function during differentiation

Myc proteins are deeply involved in multiple biological processes including cell proliferation, growth, metabolism, apoptosis, differentiation, and tumorigenesis. Paradoxically, Myc proteins have been found to be capable of both inhibiting and facilitating differentiation depending on the biological context. Recently we identified a new mode of Myc regulation in differentiating muscle cells in which c-Myc protein is proteolytically cleaved by calcium-dependent calpains in the cytoplasm. This cleavage serves two purposes. First, it inactivates the transcriptional function of Myc by removing its C-terminus, a region responsible for the interaction of Myc with Max and DNA. Second, it alters cytoskeletal architecture and accelerates muscle differentiation through the activity of the remaining N-terminal cleavage product (termed Myc-nick). Here we discuss the roles and regulation of full-length Myc and Myc-nick in terminal differentiation and propose a model in which calpain-mediated cleavage of Myc operates as a functional switch.