Disease relevance of GADD45G

• In cycling retinoblastoma protein-negative (pRb-) cells, ectopic CR6 expression blocked G2/M transition, but did not prevent G1/S transition so that endoreduplication resulted [1].
• Transient transfection of GADD45 gamma cDNA with intact open reading frame sequence into the human hepatoma cells Hep-G2 resulted in dramatic growth suppression in colony formation assays [2].
• Loss of expression of GADD45 gamma, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis [3].
• Gadd45gamma is androgen-responsive and growth-inhibitory in prostate cancer cells [4].
• Additionally, GADD45gamma deficiencies caused reduced contact hypersensitivity in mice [5].

High impact information on GADD45G

• Here, we show that the expression of GADD45gamma is induced during T cell activation and that the level of expression is higher in TH1 cells than in TH2 cells [5].
• The stress-inducible molecules GADD45beta and GADD45gamma have been implicated in regulating IFNgamma production in CD4 T cells [6].
• Among the members of the GADD family of genes, GADD153, GADD45 alpha, and GADD34 displayed marked, and GADD45 gamma showed minimal induction [7].
• Our results establish MDA-7/IL-24 and GADD45alpha and GADD45gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells [8].
• Under these conditions Gadd45gamma induction strongly potentiates apoptosis [9].

Biological context of GADD45G

• In response to stress shock, GADD45G inhibits cell growth and induces apoptosis [10].
• Assignment of human GADD45G to chromosome 9q22.1-->q22.3 by radiation hybrid mapping [11].
• GADD45gamma, down-regulated in 65% hepatocellular carcinoma (HCC) from 23 chinese patients, inhibits cell growth and induces cell cycle G2/M arrest for hepatoma Hep-G2 cell lines [2].
• GADD45 gamma also reduces colony formation in other pituitary tumor-derived cell lines, AtT20 and GH4, by approximately 60% and 50%, respectively, confirming its function in controlling cell proliferation in the pituitary [3].
• In our previous microarray analysis searching for genes differentially regulated by androgens in the rat ventral prostate, we identified GADD45gamma (growth arrest and DNA damage inducible, gamma) as one of the genes up-regulated by androgens [4].

Anatomical context of GADD45G

• The MyD118, CR6, and GADD45 proteins were shown to predominantly localize within the cell nucleus [12].
• Only one single sequence change in the coding region was detected in 1 of 25 cell lines examined, indicating that genetic inactivation of GADD45G is very rare [10].
• Same as other GADD45 members, GADD45G is ubiquitously expressed in all normal adult and fetal tissues [10].
• However, E-selectin containing all six CR domains (Lec-EGF-CR6) at its COOH terminus was the most potent in blocking neutrophil or HL-60 cell adhesion to either immobilized E-selectin or cytokine-stimulated human umbilical vein endothelial cells [13].
• In addition, the adenovirus-mediated reexpression of Gadd45gamma significantly inhibited the proliferation of anaplastic thyroid carcinoma cells, ARO, FRO, and NPA cells, which was attributed to apoptosis [14].

Associations of GADD45G with chemical compounds

• The CpG island of GADD45G was identified as a target sequence during the identification of hypermethylated genes using methylation-sensitive representational difference analysis combined with 5-aza-2'-deoxycytidine demethylation [10].
• However, this up-regulation was inhibited by cycloheximide, indicating that GADD45gamma induction by androgens requires new protein synthesis [4].
• Thus, to further explore the effects of these genes on cell growth and cell viability, either in the presence or absence of extrinsic stress, we have established M1 myeloblastic leukemia and H1299 lung carcinoma cell lines, where high level ectopic expression of MyD118, Gadd45, or CR6 can be induced by isopropyl beta-D-thiogalactopyranoside (IPTG) [15].
• The Gadd45gamma (growth arrest and DNA damage-inducible) gene is activated transcriptionally by at least two kinds of agents: DNA damaging agent such as methyl methanesulfonate (MMS) and UV radiation, or cytokines such as interleukin (IL)-6, IL-2 and granulocyte colony-stimulating factor (G-CSF) [16].

Physical interactions of GADD45G

• In this work we show that also CR6 interacts with PCNA and p21 [12].

Co-localisations of GADD45G

• CRIF1 localizes exclusively to the nucleus and colocalizes with Gadd45gamma [17].

Other interactions of GADD45G

• Importantly, evidence has been obtained that interaction of CR6 with PCNA impedes the function of this protein in negative growth control, similar to observations reported for MyD118 and GADD45 [12].
• Data accumulated suggest that MyD118/GADD45/CR6 serve similar but not identical functions along different apoptotic and growth suppressive pathways [12].
• A mutant with a deletion of the central region (residues 50-76), which is conserved in the family members GADD45beta and GADD45gamma, lacked such activity [18].
• The silencing of GADD45G could be reversed by 5-aza-2'-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism [10].
• In the present study, following clone and location of human GADD45 gamma (MyDL) gene, we have found that its mRNA expression level was down-regulated in 15/23 cases of clinic hepatocellular carcinoma (HCC) by comparing the northern hybridization results between the tumor tissues and adjacent normal tissues [2].

Analytical, diagnostic and therapeutic context of GADD45G

• Although GADD45 gamma mRNA was found in normal human pituitary tissue, it was detectable in only 1 of 18 clinically nonfunctioning pituitary tumors by RT-PCR [3].
• Molecular cloning, expression, and mapping of a novel human cDNA, GRP17, highly homologous to human gadd45 and murine MyD118 [19].
• We assigned the GRP17 gene to chromosome 9q22.1-q22.2 by fluorescence in situ hybridization (FISH) [19].
• Lec-EGF-CR6 was most likely monomeric in solution, as judged by gel filtration fast protein liquid chromatography, membrane ultrafiltration, and chemical cross-linking analysis [13].
• This study demonstrates that the Gadd45gamma gene has potential use as a candidate gene for gene therapy in anaplastic thyroid cancer [14].

References