Increase in p202 Expression during Skeletal Muscle Differentiation: Inhibition of MyoD Protein Expression and Activity by p202

ABSTRACT

p202 is a primarily nuclear, interferon-inducible murine protein that is encoded by the Ifi 202 gene. Overexpression of p202 in transfected cells retards cell proliferation. p202 modulates the pattern of gene expression by inhibiting the activity of various transcription factors including NF-κB, c-Fos, c-Jun, E2F-1, and p53. Here we report that p202 was constitutively expressed in mouse skeletal muscle and that the levels of 202 RNA and p202 greatly increased during the differentiation of cultured C2C12 myoblasts to myotubes. When overexpressed in transfected myoblasts, p202 inhibited the expression of one muscle protein (MyoD) without affecting the expression of a second one (myogenin). Thus, the decrease in the level of MyoD (but not of myogenin) during muscle differentiation may be the consequence of the increase in p202 level. Overexpressed p202 also inhibited the transcriptional activity of both MyoD and myogenin. This inhibition was correlated with an interaction of p202 with both proteins, as well as the inhibition by p202 of the sequence-specific binding of both proteins to DNA. This inhibition of the expression of MyoD and of the transcriptional activity of MyoD and myogenin may account for the inhibition of the induction of myoblast differentiation by premature overexpression of p202.

ACKNOWLEDGMENTS

We are grateful to M. Aguet and Genentech Inc. for alpha/beta interferon R^0/0 mice lacking active alpha/beta interferon receptors; to C. Weissmann and H. Weber for human alpha-2/alpha-1 interferon 1-83; to M. Horwitz for the 4RCAT plasmid; to A. Lassar for the pCMV-MyoD plasmid; to E. N. Olson and B. L. Black for the MRF(wt)CAT, MRF4(mut)CAT, and pEMSVscribe-myogenin plasmids; and to N. Stewart for preparing the manuscript for publication. We also like to thank the reviewers of the original version of the manuscript for their valuable suggestions and G. Chatterjee, H. Wang, and T. Williams for reading the manuscript.

This work was supported by the NIH NIAID research grant R37-AI12320.