ROLE OF INSULIN-LIKE GROWTH-FACTORS AND MYOGENIN IN THE ALTERED PROGRAM OF PROLIFERATION AND DIFFERENTIATION IN THE NFB4 MUTANT MUSCLE-CELLLINE

In the present study we used the mutant muscle cell line NFB4 to study the balance between proliferation and myogenic differentiation. We sh ow that removal of serum, which induced the parental C2C12 cells to wi thdraw from the cell cycle and differentiate, had little effect on NFB 4 cells, Gene products characteristic of the proliferative state, such as c-Jun, continued to accumulate in the mutant cells in low serum, w hereas those involved in differentiation, like myogenin, insulin like growth factor II (IGF-II), and IGF-binding protein 5 (IGFBP-5) were un detectable, Moreover, NFB4 cells displayed a unique pattern of tyrosin e phosphorylated proteins, especially in low serum, suggesting that th e signal transduction pathway(s) that controls differentiation is not properly regulated in these cells, Treatment of NFB4 cells with exogen ous IGF-I or IGF-II at concentrations shown, to promote myogenic diffe rentiation in wild-type cells resulted in activation of myogenin but n ot MyoD gene expression, secretion of IGFBP-5, changes in tyrosine pho sphorylation, and enhanced myogenic differentiation. Similarly, transf ection of myogenin expression constructs also enhanced differentiation and resulted in activation of IGF-II expression, showing that myogeni n and IGF-II cross-activate each other's expression. However, in both cases, the expression of Jun mRNA remained elevated, suggesting that I GFs and myogenin cannot overcome all aspects of the block to different iation in NFB4 cells.