GADD45 Signaling


Pathway Description

Genotoxic stress is a ubiquitous type of stress that cells are inevitably exposed to over the lifespan of an organism. Many environmental agents and agents produced by endogenous processes can generate reactive oxygen species and other radicals, and these reactive molecules can damage DNA in cells. A major mediator in the cellular response to DNA damage is the p53 tumor suppressor protein, which is activated by ATM/ATR kinases. Under conditions of hypoxia and nutrient deprivation, p53 is stabilized and accumulates, resulting in the induction of p53 target genes. (20940128)The GADD45 (Growth Arrest and DNA Damage-inducible 45) family of genes are significant p53 target genes and carry out some of its programs of cell arrest and rapair. The proteins encoded by this family include GADD45α, GADD45β, and GADD45γ, each characterized by specific inducible patterns of expression. GADD45α is induced in a p53-dependent manner by ionizing radiation, and its expression is augmented by p53 under UV radiation or when cells are treated with DNA-damaging agents such as methylmethane sulfonate. GADD45α can also be induced in a p53-independent manner by BRCA1. Under normal conditions, ZNF350 (also known as ZBRK1) represses GADD45α expression by associating with BRCA1. However, ZNF350 undergoes degradation when cells are exposed to UV radiation, leading to de-repression and induction of GADD45α by BRCA1 and associated transcriptional regulators such as OCT1 (POU2F1) and NF-YA. GADD45β is upregulated by TGF-β, which induces growth arrest and apoptosis in myeloid cells. GADD45γ is an immediate-early gene that is induced in T-cells in response to IL-2. (22515981)

GADD45 proteins are involved in a variety of stress and growth regulatory mechanisms, including DNA replication and repair, G2/M checkpoint control, and apoptosis. In response to DNA damage, GADD45 expression protects cell survival by inducing cell cycle arrest and providing the cells an opportunity to repair DNA. GADD45 binds to several proteins involved in these processes, including PCNA, the cell cycle kinase inhibitor p21, and CDC2. GADD45 physically interacts with CDC2 and inhibits the Cyclin B1-CDC2 kinase complex. However, upon sustained stress, GADD45 acts as an initiator of JNK/p38 MAPK signaling via its activation of an upstream kinase, MAP3K4 (also known as MEKK4), eventually resulting in apoptosis. (9827804)

Paradoxically, in some cancer cells, GADD45β is induced by NF-kB downstream of cytokine signaling, and plays a pro-survival role by interacting with and blocking the catalytic activity of MKK7, consequently downregulating pro-apoptotic signaling by JNK. (25314077) (Upgraded 09/2021)