well as its effect on gemcitabine response in a SNP-dependent manner. There has been an increased interest in FKBP51 over the past decade, especially in terms of its implications in psychiatry or psychological disorders. This is mainly due to its chaperone role in a complex with HSP90 and GR and its role in responsiveness to glucocorticoids. Our laboratory previously reported a novel function of FKBP51 and its role in cancer in response to chemotherapy, particularly treatment with cytidine analogues, gemcitabine and cytarabine. FKBP5 SNPs have already been implicated in regulating treatment response in cancer, such as acute myeloid leukemia. In the study by Mitra et al. in which patients were treated with PBTZ 169 cytarabine, another cytidine analogue, it was shown that an intronic SNP, rs3798346, was significantly associated with event free and overall survival, indicating that FKBP5 polymorphisms might contribute to drug 19053768 treatment response. In summary, the present study provides additional evidence suggesting that SNPs in FKBP5 might contribute to gemcitabine response in the treatment of pancreatic cancer. Although our study needs to be validated in a large cohort, it indicates that rs73748206 could potentially be a novel biomarker to predict patient response to gemcitabine therapy and represents a step toward the individualized chemotherapy of pancreatic cancer. FKBP5 Variation and Gemcitabine Response in Cancer 8 FKBP5 Variation and Gemcitabine Response in Cancer human GR antibody or immunoglobulin G control. The inputs for the variant and wild type were 22912405 PCR amplification products of pools of sheared DNA from the entire genome. Right panel is a ChIP qPCR analysis as % of input, shown as fold change relative to IgG. SNP-related differences in relative FKBP5 and GR gene expression after exposure to dexamethasone for 24 h in variant and WT cells; p-value,0.05. SNP-related differences in FKBP5 and GR expression, and gemcitabine response in variant, n = 1, and WT, n = 3, cell lines. Data is representative of three independent experiments; p-value,0.05. doi:10.1371/journal.pone.0070216.g003 Nedd8 is a ubiquitin-like protein that covalently modifies the cullin subunits of the cullin-RING complexes to turn on their activities as E3 ubiquitin ligases . The E1 enzyme specific for Nedd8, also known as Nedd8 activating enzyme, catalyzes the condensation of ATP with the Cterminal carboxylate of Nedd8 to form a Nedd8-AMP conjugate. The activated Nedd8 is then captured by a catalytic Cys residue of NAE to form a Nedd8,NAE thioester conjugate. Subsequently a thioester exchange reaction leads to the transfer of Nedd8 from NAE to the E2 enzyme that carries Nedd8 to cullin for its modification. UB has its own set of one or two E1s and several dozen E2s that activate and transfer UB following the same mechanism; the E1 enzymes specific for UB catalyze the formation of UB,E1 conjugates followed by UB transfer to E2s to form UB,E2 conjugates. The UB,E2 conjugates are then bound to the E3 enzymes such as the cullin-RING complexes to deliver UB to the substrate proteins recruited by the E3s. Previously it was thought that the E1E2 cascade for Nedd8 modification and the E1E2E3 cascades for UB modification do not cross 
react. However, it was recently reported that Nedd8 can enter the E1E2E3 cascades for UB transfer that results in the neddylation of the proteins targeted by E3 UB ligases. It was also found that mutations at the UB C-terminus enable UB to be efficie
Posted inUncategorized