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. At basal conditions, the expression levels of the Gadd45 family members are relatively low, but they are highly inducible upon a wide plethora of stressful stimuli, both physiological and environmental.
A decreased ability to cope with stress is one of the hallmarks of aging. Resistance to stress is one of the important determinants of animal survival and longevity. The Gadd45 proteins are implicated in many basic processes shown to be intimately linked to aging and age-related diseases (ARDs), including DNA repair, maintaining genome stability, epigenetic regulation, cell cycle arrest, cellular senescence, apoptosis, cell survival, inflammatory responses and immunity, and embryogenesis.
Aging is the major risk factor for cancer, and incidence of breast, prostate, colon, lung, stomach, bladder and skin cancer dramatically increases with age. The anti-tumor activity of Gadd45 was shown both in vitro and in vivo studies. For example, ectopic expression of Gadd45 members blocks cell growth by arresting the cells at the G2/M phase and/or induces apoptosis in several human tumor cell lines such as M1 myeloblastic leukemia, H1299 lung carcinoma, HeLa cervical cancer, RKO colon carcinoma, and in non-transformed NIH3T3 mouse embryonic fibroblasts. The silencing of Gadd45 in cancers could be greatly attributed to epigenetic changes that typically occur with advanced age. In particular, promoters of many tumor suppressors were found to be hypermethylated in aging, with subsequent transcriptional gene silencing.
The links between LAGs and Gadd45s make them highly probable candidates for the control of life span. In view of its functions, it seems reasonable that over-expression of Gadd45 might promote longevity, in particular, by increasing the efficiency of DNA repair. Indeed, an opposite situation caused by mutations in the DNA repair genes may lead to hereditary syndromes of premature aging.