Dominant-negative but not gain-of-function effects of a p53.R270H mutation in mouse epithelium tissue after DNA damage.
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.
Wijnhoven
Susan W P
SW
Laboratory of Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, Bilthoven, the Netherlands.
Speksnijder
Ewoud N
EN
Liu
Xiaoling
X
Zwart
Edwin
E
vanOostrom
Conny Th M
CT
Beems
Rudolf B
RB
Hoogervorst
Esther M
EM
Schaap
Mirjam M
MM
Attardi
Laura D
LD
Jacks
Tyler
T
van Steeg
Harry
H
Jonkers
Jos
J
de Vries
Annemieke
A
D000818:Animals; D003001:Cloning, Molecular; D004249:DNA Damage / Q000502:physiology*; D004848:Epithelium / Q000502:physiology / Q000528:radiation effects; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020125:Mutation, Missense; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D012867:Skin / Q000378:metabolism / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics*; D013471:Sunburn / Q000209:etiology / Q000235:genetics / Q000473:pathology; D014466:Ultraviolet Rays