Mammalian GADD34, an Apoptosis- and DNA Damage-inducible Gene

Abstract

The mammalian cellular response to genotoxic stress is a complex process involving many known and probably many as yet unknown genes. Induction of the human DNA damage-and growth arrest-inducible gene, GADD34, by ionizing radiation was only seen in certain cell lines and correlated with apoptosis following ionizing radiation. In addition, the kinetics and dose response of GADD34 to ionizing radiation closely paralleled that of the apoptosis inhibitor, BAX. However, unlike BAX, the GADD34 response was independent of cellular p53 status. The carboxyl terminus of GADD34 has homology with the carboxyl termini of two viral proteins, one of which is known to prevent apoptosis of virus infected cells. The association of GADD34 expression with certain types of apoptosis and its homology with a known apoptosis regulator suggests that GADD34 may play a role in apoptosis as well.

Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress

“…Lymphoid and myeloid human cancer cell lines, which undergo rapid apoptosis following ionizing radiation, also induce BAX and BCL-X L (Zhan et al, 1996a) in a p53-dependent manner, while cells resistant to apoptosis, predominantly ®broblastoid cell lines, do not. MCL-1 , GADD34 (Hollander et al, 1997), and c-JUN (Sherman et al, 1990) are also induced predominantly in cell lines prone to apoptosis, but without the requirement for wild-type p53 function.…”

“…For instance, the p53-dependent increase in transcription of GADD45 in response to ionizing radiation is thought to be mediated through a consensus p53 binding site in the third intron of the gene (Hollander et al, 1993;Kastan et al, 1992). However, p53 has also been shown to play a role in the induction of GADD45 transcription in response to other DNA-damaging stresses, such as MMS and UV radiation, through a WT1/Egr1 site recently identi®ed in the promoter (Zhan et al, 1998b).…”

Myc suppresses induction of the growth arrest genes gadd34, gadd45, and gadd153 by DNA-damaging agents

“…While the promoter is unresponsive to IR, a p53-binding element has been identi®ed in the third intron of gadd45 (Hollander et al, 1993;Kastan et al, 1992). This site is a likely mediator of the p53-dependent element of gadd45 regulation.…”

Activation ofGadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors

“…DNA damage can produce a number of cellular effects including enhanced DNA repair, mutagenesis, transient cell cycle arrest, necrosis and apoptosis. In addition to other types of DNA damage, Gadd34 was shown to be induced by ionizing radiation (IR) but only in cells which undergo rapid IR-induced apoptosis [2]. In addition, the mouse homolog of Gadd34, MyD116, was found to be induced coincident with apoptosis onset after differentiation of myeloid cells [3,4].…”