Overexpression of OATP1B3 confers apoptotic resistance in colon cancer.

Organic anion transporting polypeptide 1B3 (OATP1B3, SLCO1B3) is normally expressed in hepatocytes. In this study, we showed frequent overexpression of OATP1B3 in colorectal adenocarcinomas. Quantitative reverse transcription-PCR analysis of 17 colon tumors indicated tumoral overexpression of OATP1B3 by approximately 100-fold, compared with 20 normal colon samples (P < 0.

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

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.

DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors.

p73 has significant homology to p53. However, tumor-associated up-regulation of p73 and genetic data from human tumors and p73-deficient mice exclude a classical Knudson-type tumor suppressor role. We report that the human TP73 gene generates an NH(2) terminally truncated isoform.

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

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.

Disrupting the p53-mdm2 interaction as a potential therapeutic modality.

P53 and mdm2 are linked to each other through a negative feedback loop. P53 transactivates mdm2, but mdm2, in turn, is a major opponent of p53. Mdm2 promotes p53 degradation through a ubiquitin-dependent pathway on 26S proteasomes and is thought to be largely responsible for the very low levels of p53 protein in unstressed cells.