2',5'-Oligoadenylate synthetase (2',5'-OAS) was discovered and characterized as an interferon (IFN)-induced enzyme that in the presence of double-stranded (ds) RNA converts ATP into 2',5'-linked oligomers of adenosine with the general formula pppA(2'p'A)n, n > or = 1. The product is pppG2'p5'G when GTP is used as a substrate. Now, 20 years later, this activity is attributed to several well-characterized, homologous, and IFN-induced proteins in human cells. Three distinct forms of 2',5'-OAS exist, small, medium, and large, which contain 1, 2, and 3 OAS units, respectively, and are encoded by distinct genes clustered on the 2',5'-OAS locus on human chromosome 12. Recently, other IFN-induced proteins homologous to the OAS unit but devoid of the typical 2',5'-OAS catalytic activity have been described. These OAS-related proteins are encoded by a gene located at the proximity of the 2',5'-OAS locus. These findings illustrate the apparent structural and functional complexity of the human 2',5'-OAS family.

Mitochondrial membrane permeabilization (MMP) is a ratelimiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormonedependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondriontargeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization. (Cancer Res 2006; 66(18): 9143-52)

-1271, 1999). In the present study we analyzed whether the resistance of UHCV-11 cells to IFN could also be attributed to inhibition of PKR. Confocal laser scanning microscopy showed no colocalization of PKR, which is diffuse throughout the cytoplasm, and the induced HCV proteins, which localize around the nucleus within the endoplasmic reticulum. The effect of expression of HCV proteins on PKR activity was assayed in a reporter assay and by direct analysis of the in vivo phosphorylation of eIF2␣ after treatment of cells with poly(I)-poly(C). We found that neither PKR activity nor eIF2␣ phosphorylation was affected by coexpression of the HCV proteins. In conclusion, expression of HCV proteins in their biological context interferes with the development of the antiviral action of IFN. Although the possibility that some inhibition of PKR (by either NS5A or another viral protein) occurs at a very localized level cannot be excluded, the resistance to IFN, resulting from the expression of the HCV proteins, cannot be explained solely by inhibition of the negative control of translation by PKR.