title: Status of the mdm-2 and waf-1 genes in mouse epidermal jb6 variants harboring wild-type p53 - a p53-independent induction of waf-1.
abstract: Mutational inactivation of the p53 tumor suppressor gene has been found not to be involved in preneoplastic-to-neoplastic progression in mouse JB6 variants. To examine the role of an inactivated p53 pathway in this tumor promotion/progression model, we have studied the possible alteration of the MDM-2 oncogene, a gene whose product binds to and inactivates p53, and WAF-1 tumor suppressor gene, a gene transcriptionally controlled by p53 that mediates p53 tumor suppression. Alteration of either of these two genes might mimic p53 inactivation in cells expressing wild-type p53. Northern analysis revealed that MDM-2 expression was, in general, upregulated in neoplastic JB6 cells as compared with preneoplastic cells. This higher expression was not due to the gene amplification. Mutational analysis of WAF-1 revealed a) no point mutation in neoplastic cells; b) two polymorphic sites; and c) three nucleotide disagreements with the published sequence. Expression of the WAF-1 gene was also found to be, in general, higher in neoplastic cells, and induced by TPA and/or TNF-alpha in a p53-independent manner. The overall induced level of WAF-1 mRNA was higher in apoptosis sensitive cells after TPA/TNF-alpha treatment, suggesting a role of WAF-1 in mediating apoptosis. We conclude from this study that a) there is no evidence for mutational inactivation of WAF-1 that might mimic p53 inactivation in the JB6 model; b) elevated expression of MDM-2 and/or WAF-1 might be involved in neoplastic progression; and c) there is a p53-independent pathway controlling WAF-1 expression which may mediate p53-independent apoptosis.
authors.affiliation: NCI,VIRAL CARCINOGENESIS LAB,CELL BIOL SECT,FREDERICK,MD. FREDERICK CANC RES & DEV CTR,PROGRAM RESOURCES INC DYNCORP,CTR BIOL CARCINOGENESIS & DEV,FREDERICK,MD. GEORGETOWN UNIV,SCH MED,DEPT BIOCHEM & MOLEC BIOL,WASHINGTON,DC.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: Z
authors.initials: Z
authors.lastname: Dong
authors.forename: J
authors.initials: J
authors.lastname: Jackman
authors.forename: G
authors.initials: G
authors.lastname: Hegamyer
authors.forename: H
authors.initials: H
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Colburn