Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The promoter region of the epidermal growth factor (EGF) receptor has been identified by in vitro transcription using EGF receptor genomic DNA fragments as template and by primer extension and nuclease S1 mapping using EGF receptor mRNA. Six transcriptional start sites were identified. DNA sequence analysis shows that the promoter region contains neither a "TATA box" nor a "CAAT box," has an extremely high G+C content (88%), and contains five CCGCCC repeats and four (TCC)TCCTCCTCC repeats. This promoter region is situated close to or within a DNase I-hypersensitive site in A431 human epidermoid carcinoma cells, which overproduce the EGF receptor. The EGF receptor gene promoter has some resemblance to the promoter of the hydroxymethylglutaryl-CoA reductase gene and the early promoter of simian virus 40. This similarity may offer a clue to the mechanism by which the receptor gene is regulated.
 ...
PMID:Characterization and sequence of the promoter region of the human epidermal growth factor receptor gene. 299 99

Mevalonate metabolites play an essential role in transducing epidermal growth factor (EGF) receptor (EGFR)-mediated signaling, as several of these metabolites are required for the function of this receptor and the components of its signaling cascades. Thus, the depletion of mevalonate metabolites may have a significant effect on EGFR function. Lovastatin is a specific and potent inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Targeting 3-hydroxy-3-methylglutaryl CoA reductase using lovastatin induces a potent tumor-specific apoptotic response in a variety of tumor types at therapeutically achievable levels of this drug. The effects of lovastatin on EGFR function and the potential combination effects with EGFR tyrosine kinase inhibitors, such as gefitinib, were evaluated. Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation and its downstream signaling cascades by 24 hours. Combining lovastatin and gefitinib showed enhanced inhibition and cooperative cytotoxicity in a variety of cell lines that included all eight squamous cell carcinomas, four non-small cell lung carcinoma, and four colon carcinoma cell lines tested. Isobologram analyses confirmed that this combination was synergistic, inducing a potent apoptotic response. A phase I study has shown the safety and potential clinical benefit of high-dose lovastatin in patients with recurrent squamous cell carcinoma. The use of lovastatin, which is metabolized by CYP3A4, is contraindicated with drugs, such as gefitinib and erlotinib, which are also metabolized by CYP3A4 due to greatly enhanced toxicity. Rosuvastatin, a relatively novel potent mevalonate pathway inhibitor that is not metabolized significantly by CYP3A4, is a more appropriate statin to combine with either erlotinib or gefitinib. The combination of erlotinib and rosuvastatin has been proposed for a phase I/II study in advanced non-small cell lung carcinoma.
 ...
PMID:Strategies to enhance epidermal growth factor inhibition: targeting the mevalonate pathway. 1685 22