The liver-specific tumor suppressor STAT5 controls expression of the ROS generating enzyme NOX4 and the pro-apoptotic proteins PUMA and BIM

摘要

Loss of STAT5 from liver tissue results in hepatosteatosis and enhanced cell proliferation. This study now demonstrates that liver-specific Stat5-null mice develop severe hepatosteatosis as well as hepatocellular carcinomas at 17 months of age even in the absence of chemical insults. To understand STAT5’s role as tumor suppressor we have identified and investigated new STAT5 target genes. Expression of Nox4, the gene encoding the Reactive Oxygen Species (ROS) generating enzyme NOX4, was induced by growth hormone through STAT5. In addition, the genes encoding the pro-apoptotic proteins PUMA and BIM were induced by growth hormone through STAT5, which bound to GAS motifs in the promoter regions of all three genes. We further show that STAT5-induced activation of Puma and Bim was dependent on NOX4. Treatment of mice with TGF-β, an inducer of apoptosis, resulted in cleaved caspase 3 in control but not in liver-specific Stat5-null mice. This study for the first time demonstrates that cytokines through STAT5 regulate the expression of the ROS generating enzyme NOX4 and key pro-apoptotic proteins. We propose that STAT5 harnesses several distinct signaling pathways in liver and thereby functions as a tumor suppressor. Besides suppressing the activation of STAT3, STAT5 induces the expression of pro-apoptotic genes and the production of ROS.