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

Y. Sun, Z. Dong, J. Jackman, G. Hegamyer, H. Kim, K. Sithanandam, N. H. Colburn

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5 Scopus citations

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-α in a p53-independent manner. The overall induced level of WAF-1 mRNA was higher in apoptosis sensitive cells after TPA/TNF-α 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.

Original languageEnglish (US)
Pages (from-to)465-471
Number of pages7
JournalInternational Journal of Oncology
Volume6
Issue number2
DOIs
StatePublished - 1995

Keywords

  • Apoptosis
  • MDM-2/WAF-1 expression
  • MRNA transcripts
  • Point mutation
  • TPA/TNF-α regulation
  • Tumor promotion/progression

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