Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage.

Shirangi TR, Zaika A, Moll UM
FASEB J. 2002 16 (3): 420-2

PMID: 11790725 · DOI:10.1096/fj.01-0617fje

The principal regulator of p53 stability is HDM2, an E3 ligase that mediates p53 degradation via the ubiquitin-26S proteasome pathway. The current model holds that p53 degradation occurs exclusively on cytoplasmic proteasomes and hence has an absolute requirement for nuclear export of p53 via the CRM-1 pathway. However, proteasomes are abundant in both cytosol and nucleus, and no studies have been done to determine under what physiological circumstances p53 degradation might occur in the nucleus. We analyzed HDM2-mediated degradation of endogenous p53 in the presence of various nuclear export inhibitors of CRM-1, including leptomycin B (LMB), a noncompetitive, specific, and fast-acting inhibitor; and HTLV1-Rex protein, a potent competitive inhibitor. We found that significant HDM2-mediated p53 degradation took place in the presence of LMB or HTLV1-Rex, indicating that endogenous p53 degradation occurs locally in the nucleus, in parallel to cytoplasmic degradation. Moreover, p53 null cells that coexpressed export-defective mutants of p53 and HDM2 retained partial competence for p53 degradation. It is important that nuclear degradation of p53 occurred during the poststress recovery phase of a p53 response, after DNA damage ceased. We propose that the capability of local p53 degradation within the nucleus provides a tighter and faster control during the down-regulatory phase, when an active p53 program needs to be turned off quickly.

MeSH Terms (17)

Active Transport, Cell Nucleus Animals Cell Line Cell Nucleus Cytoplasm DNA Damage Down-Regulation Gene Products, rex Kinetics Models, Biological Mutation Nuclear Localization Signals Nuclear Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-mdm2 Transfection Tumor Suppressor Protein p53

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