Reciprocal regulation via protein-protein interaction between c-myc and p21(cip1/waf1/sdi1) in DNA replication and transcription

The c-myc protooncogene product (c-Myc) is a transcription factor and is ra pidly induced in resting cells following various mitogenic stimuli. c-Myc i s thus suggested to play an important role in the transition from quiescenc e to proliferation. Despite numerous studies, including those on the connec tion between cyclin E/cyclin-dependent kinase 2 and c-Myc, little has been clarified about c-Myc in terms of the cell cycle regulation. Here we show t hat c-Myc can directly bind to the carboxyl-terminal region of the cyclin-d ependent kinase inhibitor p(21cip1/waf1/sdi1) and thus partially relieves t he p21 of the inhibitory effect on DNA synthesis directed by the proliferat ing cell nuclear antigen-dependent DNA polymerase delta. As for transcripti on, on the other hand, the p21 binding to the Myc box II region of c-Myc bl ocks c-Myc-Max complex formation on the E-box and thereby suppresses the tr anscriptional activation from the E-box by c-Myc. These results suggest tha t c-Myc activates DNA replication via inactivation of p21 and that p21, vic e versa, represses the transcriptional activity of c-Myc. The balance of th e reciprocal inactivation between c-Myc and p21 may determine the course of cellular processes such as cell proliferation, differentiation, and apopto sis.