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Caspase-8/-10 associated RING domain proteins (CARP) 1 and 2 provide an additional layer of regulation of p53 through its degradation and the stabilization of MDM2. Degradation of p53 by CARPs requires the integrity of the RING domain and is abrogated by proteasome inhibitors. Overexpressed CARPs accelerate p53 turnover, repressing p53-mediated cell death, and knockdown of CARPs stabilizes p53, permitting p53-mediated growth arrest. Intriguingly, unlike MDM2, CARPs also interact with and ubiquitinate p53 phosphorylated at serine 20 (phospho-p53-ser20). Levels of endogenous CARP2 inversely correlate with those of chemo-induced phospho-p53-ser20 in H460 and PA-1 cells, resulting in more cell death in cells with higher phospho-p53-ser20 levels. In addition, CARPs extend the MDM2 protein half-life, and this stabilization of MDM2 is not due to inhibition of auto-ubiquitylation. Knockdown of CARPs reduces MDM2 levels in p53-null cells. In seven of ten different tumor cell lines examined, levels of CARPs positively correspond to those of MDM2. Taken together, CARPs, as novel regulators, not only play roles similar to MDM2, a known major negative regulator of p53, but also regulate phospho-p53-ser20. Therefore, our data provide novel insights in regulation of p53 by a novel negative regulator.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]