24, 27, 28 In addition, BIM was also required for tumor cell apoptosis induced by a vascular endothelial growth factor A antagonist.29 Roles for BIM and PUMA in suppressing oncogenesis have been described for B cell leukemias30 and intestinal cells,31, 32 respectively. In those cases, BIM and PUMA exerted a strong apoptotic effect, and their loss led to enhanced

tumorigenesis. Although STAT5 directly controls the expression of p15INK4B,25 PUMA, and BIM (Fig. 8), it can also exert its function through activating another direct downstream Proteasome inhibitor target gene Nox4, which encodes NOX4, a key regulator of ROS.18, 20 We further provide evidence for a direct link between NOX4 and PUMA and BIM. Inhibiting NOX4 activity led to decreased expression of PUMA and BIM and p15INK4B. The mechanism of this regulatory venue is still elusive. A picture is evolving that distinct

signaling pathways emerging from STAT5 contribute to the protection of hepatocytes (Fig. 8). Hyperactive GH signaling imposed by a GH transgene promoted inflammatory liver cancer in mice, and loss of STAT5 in these mice resulted in accelerated HCC.33 This study linked STAT5 to hepatoprotective genes and the aberrant activation of c-Jun in the absence of STAT5. Moreover, Mueller et al.34 reported that the combined loss of STAT5 and the glucocorticoid receptor resulted in the development beta-catenin inhibitor of frank HCC. In that study, development of HCC was associated with GH and insulin resistance and high ROS levels. Because NOX4, the enzyme generating ROS, is under STAT5 control, the source of ROS in STAT5 glucocorticoid receptor double knockout mice needs to be identified. Although loss of STAT5 is sufficient to induce hepatic steatosis and HCC, the extent to which the loss

of individual STAT5 executors (NOX4, PUMA, BIM, p15INK4B) would sensitize hepatocytes to injury and lead to pathological changes is unclear. Lastly, the molecular basis of STAT5′s cell specificity, promoting proliferation in the hematopoietic system and apoptosis in liver, remains an enigma. Although STAT5 can activate genes controlling cell proliferation, survival, and death, it is fair to propose that the relative activity of these pathways will determine whether STAT5 is an oncoprotein or a tumor suppressor. selleckchem Additional Supporting Information may be found in the online version of this article. “
“Given the clinical significance of hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus (HBV) infection, it is critical to elucidate the mechanisms regulating this process. In the present study, we found that the frequency of circulating chemokine (C-X-C motif) receptor 5 (CXCR5)+CD4+ T cells was higher in patients who had achieved HBeAg seroconversion in both cross-sectional (P < 0.001) and longitudinal (P = 0.009) studies.