Hepatitis C virus (HCV) core protein is a structural viral protein that packages the viral genomic RNA. In addition to this function, HCV core also modulates a number of cellular regulatory functions. In fact, HCV core protein has been found to modulate the expression of the cyclindependent inhibitor p21 WAF1/CIP1 and to promote both apoptosis and cell proliferation through its physical interaction with p53. Here, we studied the ability of HCV core to bind the p53-related p73 protein, its isoforms and its deletion mutants. We found that HCV core coimmunoprecipitated with p73 in HepG2 and SAOS-2 cells. Deletion mutational analysis of p73 indicates that the domain involved in HCV core binding is located between amino-acid residues 321-353. We also demonstrate that p73/core interaction results in the nuclear translocation of HCV core protein either in the presence of the p73 a or p73 b tumor-suppressor proteins. In addition, the interaction with HCV core protein prevents p73 a, but not p73 b dependent cell growth arrest in a p53-dependent manner. Our findings demonstrate that HCV core protein may directly influence the various p73 functions, thus playing a role in HCV pathogenesis.

Some hepatitis C virus (HCV) proteins, including core protein, deregulate the cell cycle of infected cells, thereby playing an important role in the viral pathogenesis of HCC. Thus far, there are only few studies that have deeply investigated in depth the effects of the HCV core protein expression on the progression through the G 1 /S and G 2 /M phases of the cell cycle. To shed light on the molecular mechanisms by which the HCV core protein modulates cell proliferation, we have examined its effects on cell cycle in hepatocarcinoma cells. We show here that HCV core protein perturbs progression through both the G 1 /S and the G 2 /M phases, by modulating the expression and the activity of several cell cycle regulatory proteins. In particular, our data provided evidence that core-dependent deregulation of the G 1 /S phase and its related cyclin-CDK complexes depends upon the ERK1/2 pathway. On the other hand, the viral protein also increases the activity of the cyclin B1-CDK1 complex via the p38 MAPK and JNK pathways. Moreover, we show that HCV core protein promotes nuclear import of cyclin B1, which is affected by the inhibition of both the p38 and the RNA-dependent protein kinase (PKR) activities. The important role of p38 MAPK in regulating G 2 /M phase transition has been previously documented. It is becoming clear that PKR has an important role in regulating both the G 1 /S and the G 2 /M phase, in which it induces M phase arrest. Based on our model, we now show, for the first time, that HCV core expression leads to deregulation of the mitotic checkpoint via a p38/PKR-dependent pathway. The hepatitis C virus (HCV)3 infection is a rapidly increasing public health problem, with millions of chronically infected patients to date. It is well known that patients with chronic disease have an increased risk of developing hepatocellular carcinoma (HCC) (1). Despite the research already done in this field, HCV-related mechanisms inducing cell transformation are still incompletely understood. Clinical observations indicate that the increased proliferation rate of hepatocytes is a major risk factor for the development of HCC (2). Several in vivo studies on hepatic biopsies reported an imbalance between the G 1 and the S phases of the cell cycle in liver cells obtained from chronic hepatitis C patients (3). Moreover, some studies revealed a G 2 /M dysfunction in hepatocarcinoma-derived cells (4). A large body of evidence has pointed to the possibility that HCV pathogenesis is due to virus-mediated disruption of several signal transduction pathways that normally regulate cell proliferation (5-7). However, the lack of appropriate cell culture systems and of suitable animal models that mimic viral propagation in humans has hampered the full understanding of HCV-dependent pathogenic mechanisms. The analysis of HCV gene product(s), responsible for the impairment of cell cycle regulation, has already suggested a main role of HCV core protein in regulating hepatocyte proliferation, making cells susceptible to cellular transforma...

Giardia duodenalis is a protozoan parasite of animals that is zoonotic. Given the capacity of this organism to spread via the faecal-oral route, animals held in overcrowded and unhygienic conditions are at high risk of infection. Faecal samples from dogs in three kennels in Rome were examined by microscopy and PCR for G. duodenalis, and the prevalence data generated were correlated with variables such as kennel identity, age of dog, length of time the dog had been kennelled and clinical signs.The overall prevalence of the parasite in the faecal samples was 20.5% and was higher in samples from the largest kennel, which had the greatest turnover of dogs, and in faecal samples from younger animals. Giardia cysts were found more frequently in diarrhoeic animals but were also found in dogs with no clinical signs. Although the finding that the majority of isolates were dog-specific rather than zoonotic genotypes suggests that the zoonotic risk from this pathogen is less than previously thought, the higher prevalence of infection in younger dogs may pose a specific public health issue as such animals are more frequently re-homed with families.

The molecular mechanism by which thyroid hormones exert their effects on cell growth is still unknown. In this study, we used chick embryo hepatocytes at different stages of development as a model to investigate the effect of the two thyroid hormones, T3 and T4, and of their metabolite T2, on the control of cell proliferation. We observed that T2 provokes increase of DNA-synthesis as well as T3 and T4, independently of developmental stage. We found that this stimulatory effect on the S phase is reverted by specific inhibitors of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (p42/44 MAPK), Ro 31-8220 or PD 98059. Furthermore, the treatment with thyroid hormones induces the activation of PKCalpha and p42/44 MAPK, suggesting their role as possible downstream mediators of cell response mediated by thyroid hormones. The increase of DNA-synthesis is well correlated with the increased levels of cyclin D1 and cdk4 that control the G1 phase, and also with the activities of cell-cycle proteins involved in the G1 to S phase progression, such as cyclin E/A-cdk2 complexes. Interestingly, the activity of cyclin-cdk2 complexes is strongly repressed in the presence of PKC and p42/44 MAPK inhibitors. In conclusion, we demonstrated that the thyroid hormones could modulate different signaling pathways that are able to control cell-cycle progression, mainly during G1/S transition.