Abstract
The Mdm2 oncoprotein mediates p53 degradation at cytoplasmic proteasomes and is the principal regulator for maintaining low, often undetectable levels of p53 in unstressed cells. However, a subset of human tumors including neuroblastoma constitutively harbor high levels of wild type p53 protein localized to the cytoplasm. Here we show that the abnormal p53 accumulation in such cells is due to a profound resistance to Mdm2-mediated degradation. Overexpression of Mdm2 in neuroblastoma (NB)(1) cell lines failed to decrease the high steady state levels of endogenous p53. Moreover, exogenous p53, when introduced into these cells, was also resistant to Mdm2-directed degradation. This resistance is not due to a lack of Mdm2 expression in NB cells or a lack of p53-Mdm2 interaction, nor is it due to a deficiency in the ubiquitination state of p53 or proteasome dysfunction. Instead, Mdm2-resistant p53 from NB cells is associated with covalent modification of p53 and masking of the modification-sensitive PAb 421 epitope. This system provides evidence for an important level of regulation of Mdm2-directed p53 destruction in vivo that is linked to p53 modification.
Highlights
26S proteasomes [7, 8]
No Deficiency of Endogenous Mdm2 Protein in Neuroblastoma Cells—To exclude the possibility that the constitutively high levels of wild type p53 protein in neuroblastoma (NB) cells are due to a lack of expression of its destabilizer Mdm2, we compared a panel of NB cells (SK-N-SH, LAN-5, IMR 32, CHP 134 and SK-N-AS) with a broad range of other human cell lines (Fig. 1A and data not shown)
In this study we investigated the mechanism responsible for the abnormal stability of wild type p53 protein, which constitutively accumulates in the cytoplasm of certain tumor cells and embryonic stem cells
Summary
26S proteasomes [7, 8]. Mdm2 functions as a p53-specific E3 ubiquitin ligase in vitro [9] and this ubiquitination probably takes place in the nucleus on the large p300/CBP protein, serving as a scaffolding [10]. Certain human tumors, including neuroblastoma [21], breast cancer [22,23,24], colon cancer [25,26,27], and retinoblastoma [28], as well as normal mouse embryonic stem cells [29], constitutively accumulate high levels of wild type p53 protein in their cytoplasm in the absence of stress.
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