The oncogenic activity of core might be related to its nuclear localization. In liver biopsy samples from HCV-infected patients, HCV core has been found mostly in the cytoplasm, being only rarely detected in the nucleus of infected hepatocytes. Nevertheless, a nuclear location of truncated core proteins was detected in tumor tissues from patients with HCVrelated hepatocarcinoma. Similarly, the nuclear accumulation of core has been observed in transgenic mice producing the HCV core protein and developing HCC. Taking into account the role of HCV core as a viral factor of major pathological significance and understanding the mechanisms regulating its subcellular distribution and trafficking are of critical importance. Several studies on transfected cells have shown the HCV core protein to be located in the cytoplasm or nucleus, depending on its length. Consistent with this dual localization, many studies have reported interactions with molecules located in either the cytoplasm or the nucleus. Our findings confirmed that, in an in vitro transfection system based on human Huh7 and HepG2 hepatoma cell lines or immortalized Fa2-N4 human hepatocytes, the aa and aa core proteins were found in both the nucleus and the cytoplasm. These proteins were found exclusively in the nuclei of non human cells and in human cells of non hepatic origin. By Fulvestrant contrast, the shorter core proteins aa and aa were found exclusively in the nucleus. Thus, the nuclear/cytoplasmic subcellular distribution of core proteins aa and aa was specific to human cells of hepatic origin. Our observations suggest that core protein may contain signals for specific transport mechanisms controlling its distribution between the nucleus and the cytoplasm that are functional in human hepatic cells. The differences in the distribution of the protein between the nucleus and cytoplasm in the cell types tested may reflect the availability and/or functionality of the carrier proteins in these cells. Indeed, the subcellular distribution of a given protein may be controlled by the differential expression of carrier proteins in various tissues or host species, and may depend on the differentiation status of the cell. The nucleocytoplasmic trafficking of various proteins and RNA is controlled by importins and exportins from the importin-b superfamily of proteins. These proteins can therefore gain entry into the nucleus only if they Torin 1 possess the appropriate NLS recognized by nuclear importin receptors, or if they react directly with the nuclear pore complex. Consistent with the nuclear localization of core in several experimental systems, three NLS have been identified in the N-terminal domain of this protein. These signals consist of clusters of basic amino acids in the aa, aa, and aa regions; they are functional and able to target core to the nucleus. For reentry into the cytoplasm, proteins must contain the sequences required for interaction with export factors, enabling them to leave the nucleus via the nuclear pore.