Proteolytic regulation of the zinc finger transcription factor YY1, a repressor of muscle-restricted gene expression.
Regulated proteolysis has been postulated to be critical for proper control of cell functions. Muscle development, in particular, involves a great deal of structural adaptation and remodeling mediated by proteases. The transcription factor YY1 represses muscle-restricted expression of the sarcomeric alpha-actin genes. Consistent with this repressor function of YY1, the nuclear regulator is down-regulated at the protein level during skeletal as well as cardiac muscle cell differentiation. However, the YY1 message remains relatively unaltered throughout the myoblast-myotube transition, implicating a post-translational regulatory mechanism. We show that YY1 can be a substrate for cleavage by the calcium-activated neutral protease calpain II (m-calpain) and the 26 S proteasome. The calcium ionophore A23187 destabilized YY1 in cultured myoblasts, and the decrease in YY1 protein levels could be prevented 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 polyubiquitinated in reticulocyte lysates. We further show that proteolytic targeting by calpain II and the proteasome involves different structural elements of YY1. This study thus illustrates two proteolytic pathways through which the transcriptional regulator can be differentially targeted under different cell growth conditions.
Walowitz
J L
JL
Department of Biochemistry, State University of New York, Buffalo, New York 14214-3000, USA.
Bradley
M E
ME
Chen
S
S
Lee
T
T
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D050981:Erythroid-Specific DNA-Binding Factors; D018507:Gene Expression Regulation, Developmental; D006868:Hydrolysis; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism*; D050986:YY1 Transcription Factor; D016335:Zinc Fingers
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D009097:Multienzyme Complexes; D012097:Repressor Proteins; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494700:Yy1 protein, rat; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex