Signal transduction mechanisms for the regulation of EGF receptor gene expression.

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1. Regulation of EGF receptor (EGFR) gene expression in a variant isolated from an EGFR-deficient small cell lung carcinoma (SCLC) cell line.Most cell lines derived from SCLC grow in an anchorage-independent manner ; they neither possess EGF binding activity nor express EGFR mRNA. A variant AD320, which grew In an anchorage-dependent manner with altered morphology, was isolated from SCLC cell line Lul34. EGFR mRNA and EGF binding activity could be detected In the varlant. Drastle change In gene expression Including a decrease of creatlne klnase B mRNA and an increase of c-mye mRNA were observed. The EGFR In the variant appeared to be an active part of the transmembrane signaling machinery since c-fos and c-jun mRNA accumulated after ISGF and a tumor promoter TPA treatment, followed by EGFR mRNA and c-myc mRNA accumulation. Thus, the Inducible regulatory mechanism for EGFR gene was activated in the variant even though the EGFR gene was constitutively expressed.2. Unique induction of EGF … More receptor phosphorylation and early-response gene expression by protein kinase C inhibitor Calpbostin-c.Calphostin-c is known to bind the regulatory domain of protein kinase C and t6 inhibit kinase activity in vitro in a light dependent fashion. We have found that calphostin-c induces unique cellular responses in a light dependent fashion when the EGF receptor hyperproducing squamous carcinoma cell line NA and the lung adenocareinoma cell line A549 were treated with tills compound. Phosphorylation of EGF receptor was observed 30 min after calphostln-c/llght treatment. Phosphoamino acid analysis revealed the receptor phosphorylation on serine and threonine residues. EGF binding activity was markedly reduced when treated under light, suggesting apparent internalization of the phosphorylated cell surface receptor. Furthermore, cal-c markedly enhoned e-fos and c-jun gene expression. These results suggest that calphostin-c induces a unique phosphorylation of EGF receptor and activate signal transduction pathway, which appears to be different from EGF- and TPA-activated pathways. Less