The primary objective of the proposed study is to determine the role of signaling through the erbB family receptor tyrosine kinases (RTKs) in multistage skin carcinogenesis in mice. In recent experiments Dr. DiGiovanni has found that diverse tumor promoting stimuli elevate expression (mRNA and protein)of ligands for the EGF receptor (EGFr) and that the EGFr becomes activated in tumor promoter treated mouse epidermis. In addition, he has found that the erbB2 receptor becomes activated in cultured keratinocytes exposed to EGF, 12-O-tetradecanoylphorbol- 13-acetate (TPA)-treated mouse epidermis, and in the epidermis of transgenic mice where the expression of human TGFa is targeted to the basal layer of the epidermis by the human keratin 14 (Kl4) promoter. Additional experiments have suggested that heterodimer formation occurs between the EGFr and erbB2 in both EGF-treated keratinocytes and in TPA-treated epidermis. Finally, he has found that the c-src kinase is activated in EGF-stimulated keratinocytes, in TPA-treated epidermis, and in the epidermis of K14.TGFa transgenic mice. In this proposal, he will test the hypotheses that i) activation of erbB2, through heterodimer formation with the EGFr, is a critical event during the tumor promotion stage of multistage carcinogenesis and in the development of autonomous growth in papillomas and ii) c-src is a critical downstream signaling component of the interaction of the EGFr and erbB2 during these processes.
The Specific Aims are: 1) To further examine changes in expression and/or activity of erbB family RTKs (erbB1, erbB2, and erbB3) and c-src during multistage skin carcinogenesis in SENCAR mice; 2) To further examine the mechanism(s) for, and consequences of, erbB2 activation in EGF-stimulated keratinocytes, tumor promoter treated epidermis, K14.TGFa mice and skin tumors and to identify downstream signaling pathways that are activated in these systems; 3) To examine the mechanisms for, and consequences of, c-src activation in EGF-stimulated keratinocytes, TPA-treated mouse epidermis, K14.TGFa mice, and skin tumors and to identify src signaling pathways activated in these systems; 4) To develop transgenic mice that overexpress either an activated form of erbB2 (erbB2*) or wild type erbB2 and to develop transgenic mice that are specifically deficient in erbB2 signaling in skin epidermis; 5) To develop transgenic mice that overexpress either an activated form of c-src (src530) or wild type c-src and to develop transgenic mice that are specifically deficient in c-src signaling in skin epidermis.
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