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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Wijnhoven SW,Speksnijder EN,Liu X,Zwart E,vanOostrom CT,Beems RB,Hoogervorst EM,Schaap MM,Attardi LD,Jacks T,van Steeg H,Jonkers J,de Vries Adoi
10.1158/0008-5472.CAN-06-4681subject
Has Abstractpub_date
2007-05-15 00:00:00pages
4648-56issue
10eissn
0008-5472issn
1538-7445pii
67/10/4648journal_volume
67pub_type
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