Notch signaling in vertebrate and invertebrate is well known for its regulatory function during cell fate decision process. Growing evidences are reported that notch signal also plays variable roles in adult life in addition to developmental program. This study proposes a link between Notch signaling and p53 function during UV-induced apoptosis. Co-expression of p53 with the intracellular domain of Notch receptor almost completely abrogated Notch signal in COS cells. We found that p53-dependent Inhibition of Notch signal resulted from the degradation of Notch protein by activated caspase-3. Cellular Notch protein was degraded in response to UV irradiation in Jurkat cells that express endogenous Notch. Notch function was repressed in SK-Hep cells in which the expression of endogenous wild type p53 was activated after UV treatment, however, Notch function was restored by Mdm2, which presumably mediates p53 degradation. Expression of p53 derivatives with point mutations which occur in human cancer, failed to lower Notch protein level and did not interfere with Notch function in COS cells. The present study implicates that tumor suppressor function of p53 involves the repression of Notch activity during tumor progression.