Novel Roles for the Jak/Stat Pathway in Regulation of Energy MetabolismEducation
- M.D., 1981, University of Virginia
- Ph.D., 1982, University of Virginia
- 1982-1985, Rockefeller University (James Darnell, Jr)
- 1985-1988, Resident, Laboratory of Pathology NCI, NIH, Bethesda, Maryland
The focus of my research for the past 20 years has been to understand the signals that are activated by interferons (IFNs) binding to their cell surface receptors that result in the biological actions of these cytokines. Initially we focused our attention on the cascades that lead to the expression of immediate early genes by incubation of cultured cells with either IFNα/β (type 1 interferons) or IFNγ (type 2 interferon). The findings from my lab along with several others resulted in the delineation of the Jak/Stat Pathway as a key cascade that regulates the expression of early response genes by not only interferons but also a variety of other cytokines.
During the past 6 years my research has focused on the regulation of immune responses and cell growth through activation of the Stat3 transcription factor. Our studies have elucidated novel functions of a small pool of the Stat3 transcription factor that is localized in mitochondria. We described the first evidence for the presence of Stat3 in mitochondria of cultured cells as well as primary tissues. In Stat3 -/- cells cellular ATP levels and the activities of complexes I and II of the electron transport chain (ETC) are decreased. In mice that do not express Stat3 in the heart there are also selective defects in the activities of these components of the electron transport chain. Furthermore, studies demonstrate that mitochondrial-localized Stat3, (mitoStat3), has an essential role in ability of Stat3 to transform cells.
We are presently focusing on the role of Stat3 in the mitochondria and how this bifunctional protein contributes to the pathogenesis of breast cancer. Using a combination of in vitro and in vivo experiments we have strong evidence that the phosphorylation state of serine 727 of mitochondrial-localized Stat3 significantly influences breast cancer growth. These studies define the role of mitochondrial Stat3 and its downstream effectors in the pathogenesis of breast cancer both in cell culture models as well as a mouse model of spontaneous breast carcinoma.
In addition to our interest in the role of Stat3 in energy balance and cancer, we also initiated a project to understand why mice with a targeted deletion of Tyk2 become obese. Tyk2 is a tyrosine kinase that is a member of the Jak/Stat family that is activated by several cytokines including interferons. Tyk2 RNA and protein expression is repressed in brown adipose tissue (BAT) and skeletal muscles of mice subject to a high fat diet. Furthermore, Tyk2 expression is also decreased in skeletal muscle (SKM) of obese individuals compared with lean patients. In contrast to white adipose tissue (WAT) which stores excess energy as triglycerides, brown adipose tissue (BAT) protects against obesity through adaptive thermogenesis. Differentiation into brown preadipocytes is defective in Tyk2-/- mice. Similarly, differentiation of skeletal muscle, which originates from a common progenitor as brown fat cells is impaired in Tyk2-deficient animals. The results of these experiments have defined a novel Tyk2/Stat3-mediated pathway that is required for the differentiation of brown adipose tissue. Experiments are in progress to identify substrates for Tyk2 that allow it to control differentiation of brown adipocytes. Publications