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Protein A001020
Author-entered Data
V1.0, Peer Reviewed
Published 8 Feb 2005
Automated Data
Not Reviewed
As At Publication
Automated Data
Not Reviewed
Latest from 6 Jun 2014

UCSD Nature Molecule Pages
Published online: 8 Feb 2005 | doi:10.1038/mp.a001020.01


Basis Sequence: Mouse

Jeffrey Hildesheim1, Albert J Fornace2

1Gene Response Section, National Cancer Institute, MD 20892, US. 2Lombardi Comprehensive Cancer Center, Georgetown University, DC 20057, US.

Correspondence should be addressed to Albert J Fornace:

The growth arrest and DNA damage-inducible gene Gadd45a (Gadd45/Gadd45alpha) was originally cloned by subtractive hybridization screening of Chinese hamster ovary cells after ultraviolet irradiation (UVR). Gadd45a belongs to a family of three genes, including Gadd45b (Myd118/Gadd45beta) and Gadd45g (CR6/OIG37/Gadd45gamma). Although all family members are transcriptionally activated by stress, Gadd45a is the only member to be activated by p53. Gadd45a expression may be induced by both genotoxic and nongenotoxic stresses. Although Gadd45a is not officially classified as a tumor suppressor, this small acidic protein is involved in numerous biological/biochemical events designed to protect the cell against tumorigenesis. Gadd45a is necessary to maintain normal UVR-induced stress MAPK signaling, which targets and regulates several cellular factors, including p53, and, consequently, activates cell cycle checkpoints, promotes apoptosis, blocks cell migration, and induces pro-inflammatory responses. The p53 effector Gadd45a modulates MAPK signaling via a positive feedback loop with both MEKK4 (MTK1) MAPKKK and p38 MAPK. Ras-induced senescence, for instance, requires Gadd45a-mediated p38 MAPK activation. In the absence of Gadd45a, the initial Ras-induced hyperproliferative response (due to ERK MAPK activation) is not counteracted by the antiproliferative effect of p38 MAPK. This lack of Gadd45a-induced p38 MAPK activation may in turn contribute to transformation. Gadd45a is directly involved in G2 checkpoint regulation through its association with Cdc2, which disrupts the Cdc2/cyclin B1 complex. Moreover, Gadd45a also contributes to the suppression of several invasion and metastasis-associated matrix metalloproteinases (MMPs) by associating with and contributing to adenomatous polyposis coli (APC) complex activity. Additionally, Gadd45a may play a role in coupling chromatin remodeling and nucleotide excision repair of UVR-damaged DNA. Along these lines, the p33 isoform of ING1, a tumor suppressor, interacts with Gadd45a and enhances repair of UVR-damaged DNA. Repair may also be stimulated by the forkhead transcription factor FOXO3a, which promotes Gadd45a expression after DNA damage.

Alternative names for this molecule: Ddit1; DNA-damage-inducible transcript 1; GADD45; Gadd45a; Gadd45alpha; Gene activated by DNA damage 45; Growth arrest and DNA damage-inducible gene Gadd45a; Growth arrest and DNA-damage-inducible 45 alpha; Growth arrest and DNA-damage-inducible, alpha

Transition Network Graph This molecule exists in 17 states and has 16 transitions between these states.

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