Simian virus 40 large T antigen targets the microtubule-stabilizing protein TACC2.

The large T antigens of polyomaviruses target cellular proteins that control fundamental processes, including p53 and the RB family of tumor suppressors. Mechanisms that underlie T-antigen-induced cell transformation need to be fully addressed, because as-yet unidentified target proteins might be involved in the process. In addition, recently identified polyomaviruses are associated with particular human diseases such as aggressive skin cancers. Here, we report that simian virus 40 (SV40) large T antigen interacts with the transforming acidic coiled-coil-containing protein TACC2, which is involved in stabilizing microtubules in mitosis. T antigen directly binds TACC2 and induces microtubule dysfunction, leading to disorganized mitotic spindles, slow progression of mitosis and chromosome missegregation. These mitotic defects are caused by N-terminal-deleted T antigen, which minimally interacts with TACC2, whereas T-antigen-induced microtubule destabilization is suppressed by overexpressing TACC2. Thus, TACC2 might be a key target of T antigen to disrupt microtubule regulation and chromosomal inheritance in the initiation of cell transformation.

High mobility group protein HMGA1 inhibits retinoblastoma protein-mediated cellular G0 arrest.

Retinoblastoma protein (RB) acts as a tumor suppressor in many tissue types, by promoting cell arrest via E2F-mediated transcriptional repression. In addition to the aberrant forms of the RB gene found in different types of cancers, many viral oncoproteins including the simian virus 40 large T antigen target RB. However, cellular factors that inhibit RB function remain to be elucidated. Here, we report that RB interacts with the high mobility group protein A1 (HMGA1), a-non-histone architectural chromatin factor that is frequently overexpressed in cancer cells. HMGA1 binds the small pocket domain of RB, and competes with HDAC1. Subsequently, overexpression of HMGA1 abolishes the inhibitory effect of RB on E2F-activated transcription from the cyclin E promoter. Under serum starvation, T98G cells had been previously shown to be arrested in the G0 phase in an RB-mediated manner. The G0 phase was characterized by growth arrest and low levels of transcription, together with the hypophosphorylation of RB and the downregulation of HMGA1. In contrast, such serum-depleted G0 arrest was abrogated in T98G cells overexpressing HMGA1. The overexpressed HMGA1 was found to form complexes with cellular RB, suggesting that downregulation of HMGA1 is required for G0 arrest. There were no phenotypic changes in HMGA1-expressing T98G cells in the presence of serum, but the persistent expression of HMGA1 under serum starvation caused various nuclear abnormalities, which were similarly induced in T antigen-expressing T98G cells. Our present findings indicate that overexpression of HMGA1 disturbs RB-mediated cell arrest, suggesting a negative control of RB by HMGA1.

Consumption of uncooked deer meat as a risk factor for hepatitis E virus infection: an age- and sex-matched case-control study.

It was reported previously food-borne transmission of hepatitis E virus (HEV) to humans from deer meat. The present study attempted to clarify whether eating uncooked deer meat is a major epidemiological risk factor for HEV infection in Kasai, a city in western Japan. In total, 45 volunteer subjects with experience of eating raw deer meat were enrolled. An equivalent number of people from the same area who had never eaten raw deer meat served as controls. The subjects and controls had comparable age and sex distributions. Serum anti-HEV IgG and anti-hepatitis A virus (HAV) IgG levels were measured in all 90 volunteers. There was no significant difference in age, overseas travel history, or rate of anti-HAV antibody positivity between the subjects and controls. Eight (17.7%) of the subjects but only one (2.2%) of the controls had measurable serum anti-HEV IgG levels (P = 0.014). Anti-HAV prevalence did not differ between the anti-HEV-positive and negative groups. The results suggest that eating uncooked deer meat is an epidemiological risk factor for HEV infection in the studied area. In countries such as Japan where deer meat is sometimes eaten raw, attention must be paid to this route of HEV infection.

Zoonotic transmission of hepatitis E virus from deer to human beings.

Zoonosis has been suggested for hepatitis E virus (HEV) infection, but so far is based only on indirect evidence. We experienced a series of cases of HEV infection among people who had eaten uncooked deer meat 6-7 weeks before. On testing, a left over portion of the deer meat, kept frozen to eat in the future, was positive for HEV RNA, whose nucleotide sequence was identical to those from the patients. Patients' family members who ate none or very little of the deer meat remained uninfected. These findings provide direct evidence for HEV infection to be a zoonosis.