Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors

DNA damage has many cellular consequences including, in some cases, apoptos is. Expression of Gadd34 was shown to be increased by ionizing radiation on ly in cells that undergo rapid apoptosis following this treatment. The effe cts of various other apoptosis-inducing agents as well as apoptosis-inhibit ing genes on regulation of Gadd34 were investigated. In many cell types, ag ents which have been reported to lead to increased intracellular ceramide l evels led to an increase in Gadd34 transcript levels. These included TNF al pha, the ceramide analog C-2 ceramide, dimethyl sphingosine and anti-Fas an tibody as well as ionizing radiation. Induction of Gadd34 by ionizing radia tion was coincident with the onset of apoptosis and increased as apoptosis progressed. In a short-term transfection assay, more than 30% of Gadd34-tra nsfected cells exhibited nuclear fragmentation by 48 hours. Apoptosis, as w ell as induction of Gadd34 by apoptotic stimuli, was attenuated by the apop tosis inhibitors, Bcl-2, cowpox virus CrmA and herpes simplex virus ICP34.5 . Thus, activation of Gadd34 is a downstream event in apoptotic signaling p athways and may directly contribute to the apoptotic process. 2001 Wiley-Li ss, Inc.