JUNB IS INVOLVED IN THE INHIBITION OF MYOGENIC DIFFERENTIATION BY BONE MORPHOGENETIC PROTEIN-2

Bone morphogenetic proteins (BMPs) constitute a family of multifunctio nal growth and differentiation factors structurally related to transfo rming growth factor-beta. BMPs were first identified by their osteoind uctive effects, inducing ectopic bone formation when implanted in skel etal muscle, and have an important role as regulators of skeletal deve lopment in vivo, In vitro, BMP-S is able to transdifferentiate myogeni c C2C12 cells into the osteoblastic phenotype, In this report, we show that the osteoinductive effects of BMP-S in C2C12 cells are mediated by bone morphogenetic protein receptor type-LA in combination with bot h activin receptor type II and bone morphogenetic protein receptor typ e II, We also analyzed the expression levels of nuclear protooncogenes to understand early transcriptional events induced by BMP-2. We show that junB is an immediate early gene induced by BMP-2 and transforming growth factor-beta. BMP-2 induces transcriptional activation of JunB expression as early as 30 min after Ligand addition, reaching maximal levels after 90 min, Increase of JunB mRNA correlates with a higher AP -1 binding activity. Furthermore, ectopic overexpression of JunB is su fficient to inhibit expression of myoblast differentiation markers in C2C12 cells, These data, taken together, show the involvement of JunB in the early steps of inhibition of myogenic differentiation induced b y transforming growth factor-beta family members.