Elsevier

Biochemical Pharmacology

Volume 59, Issue 1, 1 January 2000, Pages 43-45
Biochemical Pharmacology

BCP Symposium Presentation
Role of Gadd45 in apoptosis

https://doi.org/10.1016/S0006-2952(99)00291-9Get rights and content

Abstract

gadd45 is a p53-regulated growth arrest and DNA-damage-inducible gene that is also regulated in a p53-independent manner. Whether Gadd45 plays a direct role in apoptosis remains unclear. Microinjection of the exogenous gadd45 expression vector into human fibroblasts has been shown to cause G2 arrest but not apoptosis. Recent studies suggest that Gadd45 may mediate genotoxic stress or Brca1-induced apoptosis via activation of c-Jun N-terminal kinase (JNK) and/or p38 mitogen-activated protein kinase (MAPK). Analyses of gadd45-deficient mice and cells have revealed that Gadd45 appears to exhibit pleiotropic effects, including cell cycle arrest at G2/M, DNA damage repair, and control of genomic stability, but is not required for radiation-induced apoptosis. Furthermore, stress-induced activation of JNK and p38 MAPK is not altered in gadd45-deficient embryonic fibroblasts, suggesting that the lack of Gadd45 may not affect the JNK and p38 MAPK activity. Thus, although the evidence from gadd45-null cells suggests that Gadd45 probably does not play a direct role in genotoxic stress-induced apoptosis, more in-depth studies are needed to firmly establish this contention.

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      In addition to the aforementioned effects on cell cycle arrest, gadd45 was shown to induce the G2/M phase cell cycle checkpoint (Vairapandi et al., 2002; Wang et al., 1999), which could support our deduction that A549 cells proceeded through S phase but accumulated at the checkpoint in G2 phase after TBOEP and TDCPP insults. Specifically, studies have indicated that gadd45β can inhibit Cdk1/cyclinB1 kinase activity in vitro and in vivo, bind the Cdk1/cyclinB1 complex under the action of genotoxic agents (Jin et al., 2000), and direct different stress response pathways (Liebermann and Hoffman, 2008; Sheikh et al., 2000; Wang et al., 1999). The results of the present study suggest that gadd45β functions in the p53/p21-mediated cell cycle pathway in response to PFR-induced oxidative stress.

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