Disease relevance of Gas1

• A candidate inhibitor in diastema mesenchyme is the glycosylphosphatidylinositol-linked membrane glycoprotein Gas1 [1].
• Gas1 mutant limbs have defects in the proliferation of the AER and the mesenchyme and develop with small autopods, missing phalanges and anterior digit syndactyly [2].
• In addition, induction of gas1 also occurred in rat brain in two models of excitotoxicity: delayed neuronal death after intraperitoneal kainate injection and neuronal death in hippocampal slices after ischemia [3].
• All but Nc-1 and Gas-1 induced rabies virus neutralizing antibodies (VNAs) and protected groups of mice at very high frequencies from intramuscular (IM) or intracranial (IC) challenge with CVS or SW1 Shanghai dog street rabies virus (SRV); Nc-1 and Gas-1 were partly protective, more frequently against IM challenge [4].
• Gas1(-/-) mice exhibited microform HPE, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, gross integrity of the forebrain remained intact [5].

High impact information on Gas1

• Growth-arrest specific gene 6 (Gas6) is a vitamin K-dependent growth factor for mesangial and epithelial cells [6].
• Furthermore, ectopic expression of Gas1 in presomitic cells attenuates the response of these cells to SHH in vitro [7].
• A proline-rich motif in p53 is required for transactivation-independent growth arrest as induced by Gas1 [8].
• These findings suggest that transcriptional repression of growth arrest genes, including gas1, is one step in promotion of cell growth by Myc [9].
• By comparing syngenic endothelial cell lines, we found that Gas1 mRNA was increased by 3-fold in VE-cadherin-positive cells in comparison to VE-cadherin-null cells [10].

Biological context of Gas1

• These results implied that Gas1 alone, during the early stages of development, could not inhibit cell growth [11].
• However, in the 12.5 day heart and limb, we did find significantly more Gas1-expressing cells distributed at G0/G1 phase than Gas1-negative cells [11].
• Our data reveal that Gas1 is expressed in many regions that the cells are actively proliferating and suggest that it may have other roles during development than negatively regulating cell proliferation [12].
• Furthermore, we have cloned the chick GAS1 gene and documented the similarity and divergence of Gas1 gene expression patterns between the two species [12].
• Here, we describe for the first time the expression pattern of Gas1 during mouse embryogenesis [12].

Anatomical context of Gas1

• We show here that the growth-arrest specific gene 1 (Gas1), which is expressed in the dorsal somite, is induced by WNTs and encodes a protein that can bind to SHH [7].
• Gas1 is normally expressed throughout mandibular arch mesenchyme; however, in the absence of epithelium this expression was downregulated specifically in the diastema where ectopic Shh protein was identified [1].
• Gas1 was found heterogeneously expressed in most organ systems including the brain, heart, kidney, limb, lung, and gonad [11].
• Among the Gas genes, Gas1 is the only one that can cause growth arrest when expressed in cultured cell (Cell 70 (1995) 595; Int. J. Cancer 9 (1998) 569) [12].
• Gas1 is not expressed in growing or transformed cells, and when overexpressed in normal fibroblasts, it blocks the G0-to-S phase transition [13].

Associations of Gas1 with chemical compounds

• The gas1 (growth arrest-specific gene 1) gene, whose product is known to inhibit cell cycle progression, was induced in cultured corticohippocampal neurons committed to die after a brief exposure to NMDA [3].

Regulatory relationships of Gas1

• In contrast, gas1 overexpression in 12.5 day limb cells enhanced AP-1 response while it inhibited NFkappaB and c-myc activities [11].

Other interactions of Gas1

• (Cell 54 (1988) 787) identified six genes (Gas1 through Gas6) whose expressions are upregulated in serum-deprived NIH3T3 cells [12].
• To test whether FGF10 deficiency is an underlying cause of the Gas1 mutant phenotype, we employed a limb culture system in conjunction with microinjection of recombinant proteins [2].
• We show here that the growth arrest specific gene 1 (Gas1) is required in the mesenchyme for the normal regulation of Fgf10/Fgf8 [2].
• Through a detailed deletional analysis and site-specific mutagenesis of p53 we show that the Gas1-dependent signal transduction relies on a proline-rich region (amino acids 63-85) of murine p53 [8].
• In 10.5 day limb cells, gas1 overexpression had little effect on Ap-1, NFkappaB, and c-myc activities [11].

Analytical, diagnostic and therapeutic context of Gas1

• Growth arrest specific gene 1 (Gas1) has been implicated in inhibiting cell-cycle progression in cell culture studies (G. Del Sal et al., 1992, Cell 70, 595--607) [14].
• Failure of GTC chemoprevention caused induction of both histone H3 and Gas1 and down-regulation of CLU [15].
• Our in situ hybridization studies of limb sections and micromass cultures revealed that, during the early stages of chondrogenesis, only cells surrounding the chondrogenic condensations expressed gas1 [11].
• The antiproliferative effects of gas1 on 10.5 and 12.5 day limb cells were investigated by flow cytometry [11].

References