Structure, function, and chromosome mapping of thegrowth-suppressing human homologue of the murine gas1 gene.

Abstract

We describe the isolation, growth-suppressing activity, and chromosomal of the human homologue of the murine growth-arrest-specific gene gas). Overexpression of h-gas) Is able to block cell proliferation In the A549 lung carcinoma and the T24 bladder carcinoma cell lines. No effect was observed when h-gas) was introduced into the osteosarcoma cell line SAOS-2 and into the adenovirus-type-5 transformed cell line 293. This finding is related to our previous evidence that Simian virus 40-tnsformed NIH 3T3 cells are also refractory to murine gas) overexpression, sesing that the retinoblastoma and/or p53 gene products have an active role in medlating the growth-suppressing effect of gas). We also show that h-gas) is on chromosome 9q21.3-22

Tumor-suppressive activity of the growth arrest-specific gene GAS1 in human tumor cell lines

“…When dexamethasone was added to the GAS1-transfectant cell lines, GAS1 mRNA was expressed at high levels and there was a marked reduction in growth rate of the cells above that observed due to dexamethasone alone. These results are consistent with the suppression of proliferation observed in the transient microinjection assays of Del Sal et al (1992Sal et al ( , 1994. However, there was no change in the ability of the transfectant cells to grow colonies in semi-solid agar.…”

“…The GAS1-resistant cell line, SAOS-2, does not contain any functional RB or p53 gene products, suggesting that the activity of these genes may have a role in mediating the growth-inhibitory activity of GAS1. Similarly, transformation by adenovirus type 5 may inactivate RB and p53 in the 293 cell line, resulting in resistance to GAS1 (Del Sal et al, 1994). Over-expression of gas-1 in NIH3T3 fibroblasts also blocks proliferation in a p53-dependent manner, but the transcriptional activation function of p53 is not required for GAS1-induced growth arrest.…”

“…We have previously mapped the GAS1 gene by in situ hybridization to human chromosome bands 9q21.3-q22 (Evdokiou et al, 1993;Del Sal et al, 1994), a region frequently deleted in human tumors, particularly acute myeloid leukemia (Sreekantaiah et al, 1989) and bladder tumors (Cairns et al, 1993). Fine mapping of the deleted regions in early superficial bladder carcinomas has suggested that frequent (Ͼ50%) deletion of a tumor suppressor gene located between 9q22 and 9p12-13, a region that spans the location of the GAS1 gene, may be an initiating event in the pathogenesis of bladder cancer (Cairns et al, 1993).…”

REPORT on the Third International Workshop on Chromosome 9

“…A new gene GAS1, growth arresting factor, has been mapped to the region 9q21.3-q22 (Evdokiou et al 1993, Del Sal et al 1994 and was also localized by two colour FISH proximal to D9S12 (B. Wainwright, personal communication).…”

Genetic interactions between the hedgehog co-receptorsGas1andBocregulate cell proliferation during murine palatogenesis

“…Subsequently, GAS1 was mapped to human chromosome 9q21.3-22.1 and established as a negative cell cycle regulator and tumor suppressor [38]. The first link between Hh signaling and Gas1 was established through immunoprecipitation assays demonstrating Gas1 as capable of binding Shh and reducing its action [39].…”