Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabodmyosarcoma cells

MyoD inhibits cell proliferation and promotes muscle differentiation. A par adoxical feature of rhabdomyosarcoma (RMS), a tumor arising from muscle pre cursors, is the block of the differentiation program and the deregulated pr oliferation despite MyoD expression. A deficiency in RMS of a factor requir ed. for MyoD activity has been implicated by previous studies. We report he re that p38 MAP kinase (MAPK) activation, which is essential for muscle dif ferentiation, is deficient in RMS cells. Enforced induction of p38 MAPK by an activated MAPK kinase 6 (MKK6EE) restored MyoD function and enhanced MEF 2 activity in RMS deficient for p38 MAPK activation, leading to growth arre st and terminal differentiation, Stress and cytokines could activate the p3 8 MAPK in RMS cells, however, these stimuli did not promote differentiation , possibly because they activated p38 MAPK only transiently and they also a ctivated JNK, which could antagonize differentiation. Thus, the selective a nd sustained p38 MAPK activation, which is distinct from the stress-activat ed response, is required for differentiation and can be disrupted in human tumors.