Tissue-specific inactivation of p53 tumor suppression in the mouse

Tammy Bowman, Holly Symonds, Liya Gu, Chaoying Yin, Moshe Oren, Terry Van Dyke

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

The p53 gene is the most frequent target of structural and functional genetic mutations in human cancer. Thus, considerable effort has been devoted to mapping the functional domains of p53 with regard to their impact on tumorigenesis in vivo. Studies have shown that the carboxy-terminal domain of p53 is sufficient for transformation in vitro. To determine whether a transdominant-negative p53 protein could be used to elicit a tissue-specific p53-null effect in vivo, we tested whether a carboxy-terminal p53 fragment (amino acids 302-390) could abolish p53-dependent apoptosis in an established tumor progression model. We showed previously that loss of p53-dependent apoptosis accelerates brain tumorigenesis in a transgenic mouse model. Here, we show that the same effect can be elicited by expressing a dominant- negative p53 protein tissue specifically in the presence of wild-type p53. Transgenic mice in which pRb function has been disrupted and that coexpress a p53 carboxy-terminal dominant-negative fragment (p53DD) develop aggressive brain tumors mimicking genetic loss of p53 in this model. Inactivation of endogenous p53, which we show to be complexed with p53DD, results in a reduction in apoptosis and acceleration of tumorigenesis. These studies establish a mechanism for tissue-specific knock out of p53 function in vivo.

Original languageEnglish (US)
Pages (from-to)826-835
Number of pages10
JournalGenes and Development
Volume10
Issue number7
DOIs
StatePublished - Apr 1 1996

Keywords

  • apoptosis
  • cancer
  • cell specificity
  • p53
  • transgenic mice

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Fingerprint Dive into the research topics of 'Tissue-specific inactivation of p53 tumor suppression in the mouse'. Together they form a unique fingerprint.

  • Cite this