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Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage

Department of Pathology, State University of New York at Stony Brook, Stony Brook, New York, USA

¹Correspondence: Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA. E-mail: umoll{at}notes.cc.sunysb.edu

The principal regulator of p53 stability is HDM2, an E3 ligase mediating p53 degradation via the ubiquitin-26S proteasome pathway. Until recently, the accepted model held that p53 degradation occurs exclusively on cytoplasmic proteasomes, with an absolute requirement for nuclear export of p53 via the CRM1 pathway. However, 26S proteasomes are abundant in cytosol and nucleus. Using forced overexpression of HDM2 in mutant p53 tumor cells, we previously found that p53 degradation occurs in both the nucleus and the cytoplasm. p53 null cells coexpressing export-defective p53 and HDM2 retained partial competence for p53 degradation, challenging the obligatory export model. Because the ability of local nuclear destruction might add important control in switching off the p53 pathway, we now test this notion for physiological situations in untransfected cells and determine the significance of this regulation. Despite nuclear export blockade by leptomycin B and HTLV1-Rex protein, two potent CRM1 inhibitors, nuclear degradation of endogenous wild-type p53 and HDM2 occurs during down-regulation of the p53 response. This was seen in RKO and U2OS cells recovering from all major forms of DNA damage, including UV, -IR, camptothecin, or cisplatinum. Moreover, significant nuclear degradation of endogenous p53 and HDM2 occurs in isolated nuclear fractions prepared from these recovering cells. Furthermore, nuclear proteasomes efficiently degrade ubiquitinated p53 in vitro. Our data indicate that in nonlethal outcomes of cellular stress, when DNA damage has been successfully repaired and the active p53 response needs to be down-regulated quickly to resume normal homeostasis, both nuclear and cytoplasmic proteasomes are recruited to efficiently degrade the elevated p53 and HDM2 protein levels. The physiological significance of local nuclear destruction lies in the fact that it adds tighter control and speed to switching the p53 pathway off.—Joseph, T. W., Zaika, A., Moll, U. M. Nuclear and cytoplasmic degradation of endogenous p53 and HDM2 occurs during down-regulation of the p53 response after multiple types of DNA damage.

Key Words: p53/HDM2 • ubiquitination • proteasomes • degradation • cytoplasm • nucleus

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