During this reporting period the Laboratory of Genetics and Physiology has made progress in the understanding of mechanisms used by cytokines to control the physiology of muscle and liver and the involvement of cytokines in regulating metabolic processes and aberrant cell growth. LGP scientists have observed in previous studies that the transcription factor STAT5 is a tumor suppressor in liver tissue. Loss of STAT5 from hepatocytes results in the development of fatty livers and the establishment of hepatocellular carcinoma upon treatment of mice with chemical carcinogens. Using mouse embryonic fibroblasts as a test system, LGP scientists have uncovered that STAT5 controls the expression of the cell cycle inhibitors p15 and p21. Loss of STAT5 results in reduced expression of these genes, which in turn results in enhanced cell cycle progression. These ongoing studies are being extended to liver tissue. Over the past years LGP scientists have established a body of published work demonstrating that growth hormone controls the physiology of muscle tissue. Age-associated muscle atrophy is of major concern to an aging population. Although a significant body of work has described a role of growth hormone (GH) in accelerating the aging process, the cause of age-associated muscle atrophy is not known. Growth hormone deficient rodents are known to live dramatically longer than controls. Consistent with a role for growth hormone in accelerating aging, LGP scientist have now demonstrated that mice with defective growth hormone signaling specifically in skeletal muscle resist age associated atrophy at 20 months of age. These studies were performed in mice in which the Stat5 genes had been deleted in muscle tissue, which resulted in an essential block in growth hormone signaling. These mice were not resistant to acute, denervation-induced muscle atrophy demonstrating that the growth hormone / STAT5 signaling pathway is likely playing a specific role in aging related atrophy. To uncover the genetic underpinning of age-related atrophy, whole genome mRNA expression analysis was used in mice approximately 20 months of age. Altered expression of genes involved in aging and cell death pathways was detected. These studies are ongoing.
| Hosui, Atsushi; Kimura, Akiko; Yamaji, Daisuke et al. (2009) Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation. J Exp Med 206:819-31 |
| Klover, Peter; Chen, Weiping; Zhu, Bing-Mei et al. (2009) Skeletal muscle growth and fiber composition in mice are regulated through the transcription factors STAT5a/b: linking growth hormone to the androgen receptor. FASEB J 23:3140-8 |
