Keratinocytes derived from epidermal growth factor receptor (EGFR) deficient mice and transformed by the ras oncogene form very small tumors with a high growth fraction in vivo. Studies with ras transformed EGFR deficient keratinocytes in vitro reveal an accelerated migration rate and diminished attachment to extracellular matrix. These data are consistent with the rapid migration of BrdU labeled basal cells into the suprabasal compartment of EGFR deficient tumors and the premature entry of S phase tumor cells into the differentiating pool. Maturing keratinocytes also upregulate a p53 inducible chloride channel protein of the mitochondrial compartment, mtCLIC. Overexpression of mtCLIC causes apoptosis through a caspase activation pathway. mtCLIC is also upregulated by DNA damage induced by exposure of keratinocytes to chemical agents and by TNF a. The mitochondria of keratinocytes are also a target for PKC d. Activation of PKC d causes a decrease in mitochondrial membrane potential, activation of caspases and keratinocyte apoptosis. Inhibitors of mitochondrial electron transport can suppress this apoptotic response. Similarly, inhibitors of MAP kinases also prevent apoptosis induced by PKC d. Squamous tumor cells of mouse and human origin are susceptible to killing by overexpressing and activating PKC d using an adenoviral vector. Endogenous PKC d is inactivated in squamous tumor cells by tyrosine phosphorylation. Members of the Src family appear to be the proximal tyrosine kinases that phosphorylate PKC d. In tumor cells, Src and PKC d co- immunoprecipitate, and Src inhibitors prevent the association and inhibit PKC d tyrosine phosphorylation. - initiation, malignant conversion, p, , skin carcinogenesis, susceptibility, v-rasha,
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