THE TRANSCRIPTION ACTIVATION DOMAINS OF V-MYC AND VP16 INTERACT WITH COMMON FACTORS REQUIRED FOR CELLULAR-TRANSFORMATION AND PROLIFERATION

The amino terminus of the avian myelocytomatosis virus MC29 v-Myc onco protein contains sequences that are essential for cellular transformat ion (S. Farina, et al. J. Virol., 66: 2698-2708, 1992; S. Min and E. J . Taparowsky. Oncogene, 7:1531-1540, 1992) and for the ability to acti vate gene transcription (S. Min and E. J. Taparowsky. Oncogene, 7:1531 -1540, 1992). To investigate the molecular interactions that mediate t hese v-Myc-associated activities, we performed competition assays in w hich various regions of the v-Myc amino terminal transcription activat ion domain (TAD) were examined for their ability to inhibit transcript ion activation by v-Myc, VP16, and the myogenic regulatory factor MyoD . Overexpression of these transcriptional activators also was used to investigate whether Myc-interacting proteins were required for cellula r transformation and cell proliferation events. Our results demonstrat e that at least two distinct cellular activities interact with the v-M yc TAD and that it is the synergism between these activities that is r equired for v-Myc to function fully as a transcriptional activator. In addition, v-Myc activators squelch VP16- and MyoD-dependent transcrip tion activation, suggesting that the v-Myc TAD interacts with a compon ent of the general transcription machinery. In support of this observa tion, we found that overexpression of the v-Myc TAD inhibits ras-media ted cellular transformation as well as cell proliferation, underscorin g the critical role these amino terminal Myc-interacting factors play in regulating the physiology of both normal and transformed cells.