The aim of this research is to identify and characterize four classes of genes involved in multistage carcinogenesis. The first class includes genes associated with susceptibility to tumor promoter-induced neoplastic transformation. The second class includes genes that specify expression of tumor cell phenotype. The third class is tumor suppressor genes, and the fourth, apoptosis-causing genes. Mouse JB6 promotion-resistant (P-), promotion-sensitive (P+), and tumorigenic (Tx) JB6-derived epidermal cell lines have been found to differ in the expression of several susceptibility-related genes described in the accompanying project, Z01CP05383-10 LVC, "Membrane Signal Transduction in Tumor Promotion." The changes in expression of these genes during the progression from P- to P+ to Tx phenotypes appear to be genetically controlled in these stable variant cell lines. New variants of JB6 tumor cells show a differential cell-killing response to activators of protein kinase C or to tumor necrosis factor-alpha (TNF-alpha). The responsive cells show the non- random DNA damage that characterizes apoptosis (programmed cell death), a finding of significance for cancer treatment, as well as for tumor progression. TNF-alpha-induced AP-1 (Jun/Fos-dependent) transcription factor activity and dephosphorylation of Jun have been implicated as mediating events in TNF-induced apoptosis. Human nasopharyngeal carcinoma cell lines and a tumor from Hunan, China show the same expressed mutation in one of the "hot spots" of the tumor suppressor gene, p53. New evidence using human Saos-2 (p53 null) and mouse JB6 cell (containing wild-type p53) transfection recipients shows that the novel mutated p53 has oncogenic activity and that it functions dominantly in the presence of wild type p53 to inhibit transcriptional activation and to cause progression toward neoplastic phenotype at two stages.