Gadd 45 in stress signaling

Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. What deterministic factors dictate whether Gadd45 and partner proteins function in either cell survival or apoptosis remains to be determined. An attractive working model to consider is that the extent of cellular/DNA damage, in a given cell type, dictates the association of different Gadd45 proteins with particular partner proteins, which determines the outcome. Background The cellular response to stress The cellular response to environmental and physiological stress is very complex, encompassing a myriad of molecular pathways, with a plethora of regulators and effectors. Both environment agents [1] and physiological processes involving activated oxygen species and other reactive agents [2] can damage DNA. Genotoxic stress, resulting in DNA damage, is an inescapable aspect of life with which mammalian cells have to contend. Two common environmental agents that cause cellular injury primarily by damaging DNA are ionizing radiation, such as x-rays, and nonionizing UV radiation [1]. X-rays damage DNA primarily by generating hydroxyl radicals, also produced by oxidative stress, which alter the structure of bases, and the resulting DNA damage is repaired by various base-excision repair mechanisms [1]. Lesions caused by UV radiation are primarily cyclobutane pyrimidine dimers & 6-4 photoproducts that are repaired by nucleotide-excision repair [1]. Alkylating agents, such as methyl methanesulfonate (MMS), represent a major class of chemical agents that damage DNA [3]. Damage caused by alkylating agents is repaired by either base-excision repair mechanisms as well, or by in-situ repair [1]. Aberrations in DNA repair pathways are the major molecular pathology in several cancer prone hereditary diseases [4]. Defects in DNA repair pathways are known to be an early step in oncogenesis, accelerating its progression [47]. Paradoxically, DNA-damage inducing agents that can cause tumors, such as x-irradiation and a variety of alkylating agents, are frequently used in cancer therapy [8-11]. In recent years it became evident that both the molecular basis for the initial susceptibility of cancer cells to anticancer genotoxic drugs, and the development of treatment resistance originate from genetic lesions that alter the function of genes playing roles in negative growth control, notably in determining cell cycle arrest and apoptotic set Published: 12 September 2008 Journal of Molecular Signaling 2008, 3:15 doi:10.1186/1750-2187-3-15 Received: 22 July 2008 Accepted: 12 September 2008 This article is available from: http://www.jmolecularsignaling. com/content/3/1/15 © 2008 Liebermann and Hoffman; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.