@article {2472,
	title = {Nuclear degradation of p53 occurs during down-regulation of the p53 response after DNA damage.},
	journal = {The FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology},
	volume = {16},
	year = {2002},
	month = {2002 Mar},
	pages = {420-2},
	abstract = {<p>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.</p>
},
	keywords = {Active Transport, Animals, Biological, Cell Line, Cell Nucleus, Cytoplasm, DNA Damage, Down-Regulation, Gene Products, Kinetics, Models, Mutation, Nuclear Localization Signals, Nuclear Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, rex, Transfection, Tumor Suppressor Protein p53},
	issn = {1530-6860},
	doi = {10.1096/fj.01-0617fje},
	author = {Shirangi, Troy R and Zaika, Alex and Moll, Ute M}
}
