Ectopic expression of MyD118/Gadd45/CR6 (Gadd45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis.

The MyD118/Gadd45/CR6 gene family (also termed Gadd45beta/alpha/gamma) has been identified as genes which are rapidly induced by genotoxic agents, during terminal differentiation, as well as by apoptotic cytokines. In recent years, evidence has emerged that the proteins encoded by these genes play pivotal roles in negative growth control, including growth suppression and apoptotic cell death. However, under what physiological condition these proteins mediate either cell cycle arrest or apoptosis, and the molecular nature of apoptotic pathways involved are currently unclear. Thus, to further explore the effects of these genes on cell growth and cell viability, either in the presence or absence of extrinsic stress, we have established M1 myeloblastic leukemia and H1299 lung carcinoma cell lines, where high level ectopic expression of MyD118, Gadd45, or CR6 can be induced by isopropyl beta-D-thiogalactopyranoside (IPTG). By taking advantage of these cell lines, it was observed that in the absence of genotoxic stress, inducible expression of MyD118, Gadd45 and/or CR6 resulted in retardation of cellular proliferation and accumulation of cells in the G1 phase of the cell cycle. Ectopic expression of these proteins also was found to sensitize the cells to apoptosis induced by genotoxic agents such as UV, MMS, gamma-irradiation and VP16. Finally, evidence has been obtained that in the absence of stress, ectopic expression of MyD118/Gadd45/CR6 is insufficient to activate the MTKl/JNK/p38 stress cascade, and that enhancement of genotoxic stress induced apoptosis by these proteins may involve apoptotic pathways other than the JNK/p38 pathways.