Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ras oncogene family has been implicated in tumor resistance to ionizing radiotherapy. Using the gene-transfer model, we show here that ras expression may also affect cell responses to chemical inducers of oxidative stress. Studies involving human osteosarcoma subclones, which vary in their levels of EJras expression, revealed a tight correlation between the amounts of ras-encoded mRNA and p21 produced, and the degree of resistance to doxorubicin or hydrogen peroxide. Differences in response could not be explained by increased activity of anti-oxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione S-transferase or glutathione peroxidase. Moreover, there were no significant differences in glutathione levels. Although the resistant cells had elevated levels of gamma-glutamyl-transferase mRNA indicative of an increased rate of glutathione turnover, this elevation was not specific for ras-transfected cell lines. Lovastatin, an inhibitor of protein isoprenylation critical for p21ras membrane association and function, restored the sensitivity of ras-transformed cells to doxorubicin and hydrogen peroxide. The data indicate that pharmacological agents affecting ras expression may enhance responses of some human tumors to free-radical-mediated chemotherapies.
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PMID:Tumor resistance to oxidative stress: association with ras oncogene expression and reversal by lovastatin, an inhibitor of p21ras isoprenylation. 782 24

Progression through the cell cycle is controlled by the induction of cyclins and the activation of cognate cyclin-dependent kinases. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin induces growth arrest and cell death in certain cancer cell types. We have pursued the mechanism of growth arrest in PC-3-M cells, a p53-null human prostate carcinoma cell line. Lovastatin treatment increased protein and mRNA levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), increased binding of p21 with Cdk2, markedly inhibited cyclin E- and Cdk2-associated phosphorylation of histone H1 or GST-retinoblastoma protein, enhanced binding of the retinoblastoma protein to the transcription factor E2F-1 in vivo, and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the lovastatin-responsive element was mapped to a region between -93 and -64 relative to the transcription start site. Promoter mutation analysis indicated that the lovastatin-responsive site coincided with the previously identified transforming growth factor-beta-responsive element. These data indicate that in human prostate carcinoma cells an inhibitor of the HMG-CoA reductase pathway can circumvent the loss of wild-type p53 function and induce critical downstream regulatory events leading to transcriptional activation of p21.
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PMID:Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells. 955 23