Disease relevance of GAS1

• The human growth-arrest-specific gene GAS1 maps outside the candidate region of the gene for nevoid basal cell carcinoma syndrome [1].
• Fine mapping of the hereditary sensory neuropathy type I locus on chromosome 9q22.1-->q22.3: exclusion of GAS1 and XPA [2].
• XPA mutations have been shown to cause peripheral neuropathy, and GAS1 is related to the PMP22 gene, which is critical in the pathogenesis of two other peripheral neuropathies [2].
• Relevance of these genes (especially a decrease in GAS1 in thyroid papillary carcinoma) in various malignant pathologies has already been shown [3].
• No effect was observed when h-gas1 was introduced into the osteosarcoma cell line SAOS-2 and into the adenovirus-type-5 transformed cell line 293 [4].

High impact information on GAS1

• When gas1 is overexpressed from a constitutive promoter in quiescent cells, the serum-induced transition from the G0 to the S phase of the cell cycle is inhibited without affecting the normal early serum response [5].
• From the predicted amino acid sequence, in vitro translation of gas1 mRNA, and immunofluorescence of cells in culture, it appears that the gas1 protein is an integral plasma membrane protein whose expression is linked to growth arrest [5].
• Ectopic expression of the gas1 gene by microinjection in normal and transformed NIH 3T3 cell lines with the notable exception of SV40-transformed 3T3 cells leads to inhibition of DNA synthesis [5].
• Is GAS1 a co-receptor for the GDNF family of ligands [6]?
• GAS1, an apparently unrelated protein, exhibits homology to GFR alpha and thus we hypothesize that GAS1 can serve as an alternative receptor for GFLs [6].

Chemical compound and disease context of GAS1

• In the present study, we have analysed the effects of the transcriptionally mediated targeting of gas1 to C6 rat glioma cells [7].

Biological context of GAS1

• When a constitutively expressing GAS1 plasmid was transfected into A549 cells, no stable colonies expressing GAS1 were isolated [8].
• To investigate whether GAS1 is a tumor suppressor gene, we transfected GAS1-negative human tumor cells with GAS1 plasmids and analyzed growth characteristics of stable transfectants [8].
• Localization of the human growth arrest-specific gene (GAS1) to chromosome bands 9q21.3-q22, a region frequently deleted in myeloid malignancies [9].
• The interaction of GAS1 with the interferon-responsive promoter region in the physiological context remains to be clarified [10].
• However, deletion constructs and mutational analysis of CAT reporter gene constructs harbouring the 5'-flanking region (positions -1762 to -111) in front of the heterologous promoter revealed that the distal GAS3 site was dispensible, but that alteration of the GAS1 element rendered the promoter uninducible by IFN-gamma [10].

Anatomical context of GAS1

• Tumor-suppressive activity of the growth arrest-specific gene GAS1 in human tumor cell lines [8].
• We propose that the relative expression and localization of the two remote receptors, GFR alpha and GAS1, on the membranes of neuronal and glial cells determines whether these cells survive or undergo apoptotic death [6].
• We evaluated the GAS1 gene for its potential role in bladder cancer using single-strand conformational polymorphism to screen for mutations in GAS1 in 10 bladder cancer cell lines and 14 primary bladder tumors [11].
• Growth-regulatory activity of the growth arrest-specific gene, GAS1, in NIH3T3 fibroblasts [12].
• Immunoelectron microscopy shows that, in its mature form, Gas1 is randomly distributed over the outer leaflet of the plasma membrane and that upon antibody-induced clustering it relocalizes to caveolae [13].

Associations of GAS1 with chemical compounds

• When expression of GAS1 mRNA was induced with dexamethasone, the growth rate was greatly inhibited [12].
• In vitro experiments showed that the retroviral transfer of gas1 significantly reduces the number of viable cells, and induces apoptosis in C6 cells, through the activation of caspase-3 [14].
• Gas1p is a glycoprotein anchored to the outer layer of the plasma membrane through a glycosylphosphatidylinositol (GPI) anchor [15].

Regulatory relationships of GAS1

• However, full promoter activity requires additional regions, and in this paper we explored PRL-induced activity at sites other than GAS1 [16].

Other interactions of GAS1

• GAS1, XPA, and several other genes that map within the interval initially identified for the disease locus have been investigated and excluded from playing a pathogenic role in HSN-I [2].
• The functional similarity between GFR alpha and GAS1 extends to their role in embryogenesis, differentiation and glia maintenance, and is substantiated by overlap in their expression profile, subcellular localization and structural details [6].
• GAS1 and PTC do not seem to be frequently mutated in bladder cancer [11].
• Growth arrest-specific gene 6 (Gas6) and its receptors Rse, Axl and Mer have recently been found to be involved in a rat model of chronic allograft nephropathy (CAN) [17].
• IL-4 favored the induction of cytokines and of genes associated with cell growth arrest (GADD34, GAS-1, CIDE-A, INK4D, and BAX) and completely abolished the enhanced proliferation observed in the other 3 groups after activation [18].

Analytical, diagnostic and therapeutic context of GAS1

• Using two-colour fluorescence in situ hybridization, the GAS1 gene maps outside the interval which, by genetic analysis, has been shown to contain the NBCCS gene [1].
• Consistent with this, electrophoretic mobility shift assays detect STAT-1alpha interactions with the downstream GAS1 motif [19].
• The gene coding for the GAS1 homologue of P. pastoris was cloned by PCR, and its functionality was proven in a Saccharomyces cerevisiae GAS1 null mutant [15].
• Our results support the concept of targeted expression of gas1 as a potentially useful gene therapy strategy in the treatment of human gliomas [7].
• Transcriptionally mediated gene targeting of gas1 to glioma cells elicits growth arrest and apoptosis [7].

References