GENES INVOLVED IN PRENEOPLASTIC PROGRESSION

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The aim of this research is to identify and characterize two classes of genes involved in multistage carcinogenesis. The first class are genes that specify susceptibility to tumor promoter-induced neoplastic transformation. The second class are genes that specify expression of tumor cell phenotype. Mouse promotion sensitivity (P+) gene pro 1, previously cloned from mouse epidermal JB6 cells and sequenced, shows evidence for encoding polymerase III-catalyzed transcripts demonstrated by RNase protection and polymerase chain reaction (PCR) analysis to be a 130-mer and a 175-mer. Transcriptionally defective mutants of pro 1 produced by a novel site-directed mutagenesis procedure are being assayed for biological activity. PCR analysis has identified the promotion-insensitive (P-) homolog of pro 1 and the sequence of this is being compared with that of the P+ active no 1. Active and inactive human homologs of pro I isolated from a library of nasopharyngeal carcinoma (NPC) cells are being compared at the sequence level, with the aim of identifying activating mutations. Several sources of NPC, both Epstein-Barr virus (EBV)-positive and EBV-negative NPC'S, have been analyzed and found to show two DNA associated activities detectable in mouse JB6 recipients: (1) transfer of promotion sensitivity (P+ activity) and (2) transfer of oncogenic transformation (Tx activity). A novel transforming gene unrelated to the ras family or to some 20 other oncogenes has been cloned from NPC cells by human Alu screening of an NPC/JB6 transfectant DNA library. An mRNA of 1.7 kb is observed in NPC cells but not in mouse recipient cells. A Tx activity is also detected in colon carcinoma DNA and is being characterized using mouse JB6 recipient cells. The set of cloned oncogenes detected singly or in pairs differs from that found with NIH 3T3 cells. With the cloning of the new NPC oncogene it now becomes possible to study the cooperation between genes involved in induction of cancer and genes involved in expression of tumor cell phenotype. The hypothesis that "induction genes" cause activation of "expression "genes" will be tested.