PROTEOLYTIC REGULATION OF THE ZINC-FINGER TRANSCRIPTION FACTOR YY1, AREPRESSOR OF MUSCLE-RESTRICTED GENE-EXPRESSION

Regulated proteolysis has been postulated to be critical for proper co ntrol of cell functions, Muscle development, in particular, involves a great deal of structural adaptation and remodeling mediated by protea ses. The transcription factor YY1 represses muscle-restricted expressi on of the sarcomeric alpha-actin genes, Consistent with this repressor function of YY1, the nuclear regulator is down-regulated at the prote in level during skeletal as well as cardiac muscle cell differentiatio n. However, the YY1 message remains relatively unaltered throughout th e myoblast-myotube transition, implicating a post-translational regula tory mechanism, We show that YY1 can be a substrate for cleavage by th e calcium-activated neutral protease calpain II (m-calpain) and the 26 S proteasome. The calcium ionophore A23187 destabilized YY1 in cultur ed myoblasts, and the decrease in YY1 protein levels could be prevente d by calpain inhibitor II and calpeptin. Treatment with the proteasome inhibitors MG132 and lactacystin resulted in the stabilization of YY1 protein, which is consistent with the finding that YY1 is readily pol yubiquitinated in reticulocyte lysates. We further show that proteolyt ic targeting by calpain II and the proteasome involves different struc tural elements of YY1, This study thus illustrates two proteolytic pat hways through which the transcriptional regulator can be differentiall y targeted under different cell growth conditions.