Activated MEK1 binds the nuclear MyoD transcriptional complex to repress transactivation

To elucidate the mechanism through which MAPK signaling regulates the MyoD family of transcription factors, we investigated the role of the signaling intermediate MEK1 in myogenesis. Transfection of activated MEK1 strongly re pressed gene activation and myogenic conversion by the MyoD family. This re pression was not mediated by direct phosphorylation of MyoD or by changes i n MyoD stability or subcellular distribution. Deletion mapping revealed tha t MEK1-mediated repression required the MyoD amino-terminal transactivation domain. Moreover, activated MEK1 was nuclearly localized and bound a compl ex containing MyoD in a manner that is dependent on the presence of the Myo D amino terminus. Together, these data demonstrate that MEK1 signaling has a strong negative effect on MyoD activity via a novel mechanism involving b inding of MEK1 to the nuclear MyoD transcriptional complex.