We have previously shown that inhibition of proteasome activity leads to synchronous nucleolar translocation of mutant p53, EBNA 5 and Hsp70 in transfected SW480 cells. We have also shown that increased level of EBNA 5 enhanced the nucleolar selleck inhibitor Inhibitors,Modulators,Libraries translocation of mutant p53. More recently we found that the simultaneous presence of EBNA 5 and mutant p53 sensitizes cells for MG132 and bortezomib Inhibitors,Modulators,Libraries induced cytotoxicity. These data also suggest there is a close func tional interplay between mutant p53 and EBNA 5. PRIMA 1MET was identified as a low molecular weight compound that can enhance apoptosis in mutant p53 car rying cells, compared to the p53 null parental cells. Most p53 mutants are in complex with Hsp70 proteins.

We have recently shown that PRIMA 1MET treatment increases Hsp70 Inhibitors,Modulators,Libraries expression and nucleolar translocation, in parallel with the induction of nucleolar accumulation Inhibitors,Modulators,Libraries of mutant p53. Numerous experiments indicate that the increased apoptosis induction is accompanied by the acti vation of p53 target genes. Several lines of evi dence suggest that PRIMA 1MET can also act independently of the p53 status of the cell. It can radiosensitize prostate carcinoma cell lines with mutant or wild type p53 and p53 cells as well. Introduction of mutant p53 into p53 hepatocarcinoma cells increases sensitivity to PRIMA 1MET without the induction of p53 target genes. PRIMA 1MET is a powerful apoptosis inducing agent. Iden tification of its targets is partly hindered by the difficulties to separate its effect from the numerous molecular changes associated with cellular agony subsequent to drug treatment.

Here we show that subcellular distribution of EBNA 5 changes Inhibitors,Modulators,Libraries in parallel with mutant p53 itself upon PRIMA 1METtreatment. Similar changes in EBNA5 distri bution occur in cells that lack p53 and are therefore resist ant for p53 induced apoptosis. We propose that EBNA 5 may serve as a surrogate target that may help to elucidate the molecular action of PRIMA 1MET. Background Human cancers exhibit genomic instability and height ened drug sensitivity due to underlying defects in DNA repair or cell cycle regulation. The specific pathways affected may be predictive of the tumors drug sensitivity and clinical outcome. For some tumors, loss of one DNA repair pathway may result in hyper dependence on a sec ond, compensatory DNA repair pathway.

Therapeutic gain selleck chemicals may be achieved by inhibition of this second path way. The Fanconi Anemia pathway is a DNA repair path way required for cellular response to DNA cross linking agents such as mitomycin C and cisplatin. The thirteen known FA proteins cooperate in this pathway, leading to the monoubiquitination of the FANCD2 FANCI hetero dimer, activating DNA crosslink repair. Disruption of any of the proteins in the FA pathway, either by germline or somatic mutations, leads to the characteristic cross linker hypersensitivity and chro mosome instability.