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gadd45a

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Official Full Name
growth arrest and DNA-damage-inducible, alpha
Background
This gene is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The protein encoded by this gene responds to environmental stresses by mediating activation of the p38/JNK pathway via MTK1/MEKK4 kinase. The DNA damage-induced transcription of this gene is mediated by both p53-dependent and -independent mechanisms. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
Synonyms
GADD45A; growth arrest and DNA-damage-inducible, alpha; DDIT1; growth arrest and DNA damage-inducible protein GADD45 alpha; GADD45; DDIT-1; DNA damage-inducible transcript-1; DNA-damage-inducible transcript 1; DNA damage-inducible transcript 1 protein; gr; growth arrest and DNA-damage-inducible 45 alpha; growth arrest and DNA-damage-inducible protein 45 alpha

Gadd45a is a member of the Gadd45 family of genes that are known as stress sensors, which modulates the cellular response to multiple stress conditions, such as genotoxic and oncogenic stress. The complex role of stress sensors in monitoring tumor development is not fully understood, the best example being a variety of functions attributed to p53 in tumor development and suppression. Gadd45a is a transcriptional target for tumor suppressors p53 and BRCA1, whose loss of function play important roles in cancer development, including breast tumorigenesis.

Gadd45a, the first well-defined p53 downstream gene, is induced by a variety of DNA-damaging agents and growth arrest signals, such as hypoxia, methylmethane sulfonate (MMS), ionizing radiation (IR), UV radiation (UVR), cisplatin, medium depletion and growth factor withdrawal. It is reported that high-frequency point mutations are found in exon 4 of Gadd45a in human pancreatic cancer and the expression level of Gadd45a, combined with p53 status, significantly affects the survival of patients. There is also evidence to show Gadd45a as an abnormally methylated gene in breast cancer. The key roles of Gadd45a have been well-demonstrated in multiple cellular processes. By physically interacting with Cdc2 kinase, Gadd45a can dissociate Cdc2/cyclinB1 complex and mediate G2/M cell cycle arrest. By interacting with proliferating cell nuclear antigen (PCNA), Gadd45a is involved in DNA repair process. Furthermore, it can induce apoptosis by promoting Bim translocation to mitochondria. Recently, controversial roles of Gadd45a in the control of DNA demethylation have been reported. As a tumor-suppressor gene, Gadd45a negatively regulates cell malignancy.

Tumor progression is considered to be a complex process, in which metastasis is the main cause of death in patients with malignancy. Several classes of proteins are involved in the cell metastatic process, including integrins, cell adhesion molecules (CAMs), extracellular matrix (ECM) and matrix metalloproteinases (MMPs). Gadd45a may not only play important roles in anti-tumorigenesis but also contribute to inhibiting tumor progression. It has been noted that Gadd45a might regulate matrix metalloproteinase through p38 MAP kinase and APC complex activation. The previous study has revealed that Gadd45a maintained cell-cell adhesion and cell contact inhibition by regulating β-catenin subcellular distribution. In addition, the recent report showed that Gadd45a regulates adhesion, migration and invasion of MEF cells in vitro. Furthermore, Gadd45a affects the expression of various genes involved in ECM, cell adhesion, cell communication. However, deregulations of these genes are caused neither by genomic aberrations nor methylation status. In general, Gadd45a could be involved in tumor progression by regulating related genes expressions.

References:

  1. Tront J S, et al. Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress. Cancer Research, 2010, 70(23):9671-9681.
  2. Shan Z, et al. Gadd45a inhibits cell migration and invasion by altering the global RNA expression. Cancer Biology & Therapy, 2012, 13(11):1112-1122.
  3. Tront J S, et al. Gadd45a levels in human breast cancer are hormone receptor dependent. Journal of Translational Medicine, 2013, 11(1):131-131.
  4. Yang F. Gadd45a Suppresses Tumor Angiogenesis via Inhibition of the mTOR/STAT3 Protein Pathway. Journal of Biological Chemistry, 2013, 288(9):6552-6560.
  5. Hong L, et al. New role and molecular mechanism of Gadd45a in hepatic fibrosis. World Journal of Gastroenterology, 2016, 22(9):2779-2788.