During this reporting period the Laboratory of Genetics and Physiology has made progress and elucidated mechanisms by which cytokines control normal liver physiology and the development of liver cancer and hematopoietic malignancies through the transcription factors STAT1 and STAT5. In addition, we performed the first study that addresses the role of cytokine-induced miRNA genes in mammary gland development. Lastly, we explored the relationship between genome-wide binding of the transcription factor STAT5 and its capacity to subsequently engage in the activation of nearby genes. Liver metabolism and hepatocellular carcinoma Using mouse genetics tools LGP scientists have shown previously that the transcription factor STAT5 controls the physiology of liver tissue and that loss of STAT5 results in hepatosteatosis and hepatocellular carcinoma (HCC). We have now identified a novel mechanism used by STAT5 to act as a tumor suppressor in hepatocytes. By high throughput gene expression analyses we identified and investigated genes that are under the control of cytokines and STAT5. We showed that 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 regulated by STAT5, which bound to GAS motifs in the promoter regions of all three genes. We also demonstrated that TGF-β, an inducer of apoptosis, required STAT5 for its biological function. This study for the first time showed that cytokine signaling through STAT5 regulates the expression of the ROS generating enzyme NOX4 and key pro-apoptotic proteins. These results demonstrate that STAT5 harnesses several distinct signaling pathways in liver to exert tumor suppressor functions. In a collaborative study, it was determined that suppression of STAT1 in hepatocellular carcinoma is associated with tumor progression. Interferon (IFN) αhas been reported to be effective for prevention of HCC recurrence, but the detailed mechanisms remained elusive. The study demonstrated that tumor growth was suppressed by IFNαthrough inhibition of VEGF expression in a xenograft model and it was enhanced when Stat1-deleted cells were injected. Patients with suppressed STAT1 activity had a shorter recurrence-free survival. The studies also showed a reverse correlation between VEGF and STAT1-regulated genes expression. These results suggested IFNαas a potential candidate for prevention of vessel invasion acting through inhibition of VEGF expression. Hematopoiesis In the past we have provided insight into mechanisms by which cytokines control various aspects of hematopoiesis through the transcription factor STAT5. These studies revolved around conditional gene knock-out mice generated in LGP. LGP scientists have now participated in a study demonstrating that STAT5 is essential for the induction of CML-like leukemia by BCR-ABL1 and of polycythemia vera by mutant JAK2(V617F). STAT5 proteins are constitutively activated in malignant cells from many patients with myeloproliferative neoplasias (MPNs) but whether STAT5 is essential for the genesis of these diseases was not known. Mice with a conditional null mutation in the Stat5a/b gene locus were used to determine the requirement for STAT5 in MPNs induced by BCR-ABL1 and JAK2(V617F). Complete deletion of Stat5 prevented the development of leukemia upon transplantation. These findings identify STAT5 proteins and the genes they regulate as valid targets for therapy in these MPNs. miRNAs and mammary physiology Micro RNAs (miRNAs) are believed to be important post transcriptional regulators of messenger RNAs that modulate the physiology of cells. LGP scientists have identified miRNAs that are under cytokine-STAT5 control, suggesting a role for them in those cells that depend on the presence of STAT5. To address the relevance of specific miRNAs regulated by STAT5 we performed studies to delete specific STAT5 dependent miRNA genes. In the current reporting period we have deleted a cluster composed of several miRNAs (miR-17-92) from mammary stem cells in mice and explored the consequences on mammary development and function. Unexpectedly, mammary tissue devoid of these miRNAs underwent normal developed during pregnancy and mice were able to lactate. Thus, at least this miRNA cluster is not required for normal mammary physiology. We are in the process of evaluating the role of additional miRNAs in the mammary gland and liver.

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Hosui, Atsushi; Tatsumi, Tomohide; Hikita, Hayato et al. (2016) STAT5 plays a crucial role in hepatic lipid metabolism through regulation of CD36 expression. Hepatol Res :
Shin, Ha Youn; Willi, Michaela; Yoo, Kyung Hyun et al. (2016) Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat Genet 48:904-11
Sakamoto, Kazuhito; Wehde, Barbara L; Yoo, Kyung Hyun et al. (2016) Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling. Mol Cell Biol 36:1673-90
Yoo, Kyung Hyun; Oh, Sumin; Kang, Keunsoo et al. (2016) Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms. Mol Cell Biol 36:2108-20
Metser, Gil; Shin, Ha Youn; Wang, Chaochen et al. (2016) An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic Acids Res 44:1052-63
Lee, Jongwon; Seong, Semun; Kim, Jung Ha et al. (2016) STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis. Sci Rep 6:30977
Müller, T A; Grundler, R; Istvanffy, R et al. (2016) Lineage-specific STAT5 target gene activation in hematopoietic progenitor cells predicts the FLT3(+)-mediated leukemic phenotype. Leukemia 30:1725-33
Villarino, Alejandro; Laurence, Arian; Robinson, Gertraud W et al. (2016) Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions. Elife 5:
Alamri, Ahmad M; Kang, Keunsoo; Groeneveld, Svenja et al. (2016) Primary cancer cell culture: mammary-optimized vs conditional reprogramming. Endocr Relat Cancer 23:535-54
Haetscher, Nadine; Feuermann, Yonatan; Wingert, Susanne et al. (2015) STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling. Nat Commun 6:8928

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