twist is a potential oncogene that inhibits apoptosis

Oncogene activation increases susceptibility to apoptosis. Thus, tumorigene sis must depend, in part, on compensating mutations that protect from progr ammed cell death. A functional screen for cDNAs that could counteract the p roapoptotic effects of the myc oncogene identified two related bHLH family members, Twist and Dermol. Both of these proteins inhibited oncogene- and p 53-dependent cell death. Twist expression bypassed p53-induced growth arres t. These effects correlated with an ability of Twist to interfere with acti vation of a p53-dependent reporter and to impair induction of p53 target ge nes in response to DNA damage. An underlying explanation for this observati on may be provided by the ability of Twist to reduce expression of the ARF tumor suppressor. Thus, Twist may affect p53 indirectly through modulation of the ARF/MDM2/p53 pathway. Consistent with a role as a potential oncoprot ein, Twist expression promoted colony formation of E1A/ras-transformed mous e embryo fibroblasts (MEFs) in soft agar. Furthermore, Twist was inappropri ately expressed in 50% of rhabdomyosarcomas, a tumor that arises from skele tal muscle precursors that fail to differentiate. Twist is known to block m yogenic differentiation. Thus, Twist may play multiple roles in the formati on of rhabdomyosarcomas, halting terminal differentiation, inhibiting apopt osis, and interfering with the p53 tumor-suppressor pathway.