NOTCH SIGNALING INHIBITS MUSCLE-CELL DIFFERENTIATION THROUGH A CBF1-INDEPENDENT PATHWAY

Notch controls cell fate by inhibiting cellular differentiation, presu mably through activation of the transcriptional regulator human C prom oter Binding Factor (CBF1), which transactivates the hairy and Enhance r of split (HES-1) gene. However, we describe constitutively active fo rms of Notch1, which inhibit muscle cell differentiation but do not in teract with CBF1 or upregulate endogenous HES-1 expression. In additio n, Jagged-Notch interactions that prevent the expression of muscle cel l specific genes do not involve the upregulation of endogenous HES-1, In fact, exogenous expression of HES-1 in C2C12 myoblasts does not blo ck myogenesis. Our data demonstrate the existence of a CBF1-independen t pathway by which Notch inhibits differentiation. We therefore propos e that Notch signaling activates at least two different pathways: one which involves CBF1 as an intermediate and one which does not.