Dominant-negative but not gain-of-function effects of a p53.R270H mutation in mouse epithelium tissue after DNA damage.
Cancer Res
; 67(10): 4648-56, 2007 May 15.
Article
in En
| MEDLINE
| ID: mdl-17510390
ABSTRACT
p53 alterations in human tumors often involve missense mutations that may confer dominant-negative or gain-of-function properties. Dominant-negative effects result in inactivation of wild-type p53 protein in heterozygous mutant cells and as such in a p53 null phenotype. Gain-of-function effects can directly promote tumor development or metastasis through antiapoptotic mechanisms or transcriptional activation of (onco)genes. Here, we show, using conditional mouse technology, that epithelium-specific heterozygous expression of mutant p53 (i.e., the p53.R270H mutation that is equivalent to the human hotspot R273H) results in an increased incidence of spontaneous and UVB-induced skin tumors. Expression of p53.R270H exerted dominant-negative effects on latency, multiplicity, and progression status of UVB-induced but not spontaneous tumors. Surprisingly, gain-of-function properties of p53.R270H were not detected in skin epithelium. Apparently, dominant-negative and gain-of-function effects of mutant p53 are highly tissue specific and become most manifest upon stabilization of p53 after DNA damage.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Skin Neoplasms
/
DNA Damage
/
Genes, p53
/
Mutation
/
Neoplasms, Radiation-Induced
Type of study:
Etiology_studies
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Cancer Res
Year:
2007
Type:
Article
Affiliation country:
Netherlands