Abstract:
:There is currently much interest in the idea of restoring p53 activity in tumor cells by inhibiting Hdm2/Mdm2. However, it has remained unclear whether this would also activate p53 in normal cells. Using a switchable endogenous p53 mouse model, which allows rapid and reversible toggling of p53 status between wild-type and null states, we show that p53 is spontaneously active in all tested tissues of mdm2-deficient mice, triggering fatal pathologies that include ablation of classically radiosensitive tissues. In apoptosis-resistant tissues, spontaneous unbuffered p53 activity triggers profound inhibition of cell proliferation. Such acute spontaneous p53 activity occurs in the absence of any detectable p53 posttranslational modification, DNA damage, or p19ARF signaling and triggers rapid p53 degradation.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Ringshausen I,O'Shea CC,Finch AJ,Swigart LB,Evan GIdoi
10.1016/j.ccr.2006.10.010subject
Has Abstractpub_date
2006-12-01 00:00:00pages
501-14issue
6eissn
1535-6108issn
1878-3686pii
S1535-6108(06)00316-3journal_volume
10pub_type
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