Abstract

JAK-STAT signaling in human diseaseThe discovery of Stat proteins' key role in IFN signaling, initially described over ten years ago, provided the first molecular link of growth factor receptor stimulation to the direct activation of a transcription factor (1). Since that time a large number of growth factor receptors and some nonreceptor tyrosine kinases have been found to lead to the activation of these transcription factors (2).The contributions of individual Stat proteins to normal cytokine signaling and development have been studied in various cell culture systems and in vivo in mice made deficient for one or more of these proteins (3).This approach has identified some related roles, as well as many unique, nonoverlapping physiological roles, for the various members of the Stat family.In summary, Stat1-deficient mice are unable to respond to IFNs and are subsequently susceptible to bacterial and viral pathogens.Likewise, disruption of Stat2 gives rise to animals unable to respond to type 1 IFNs, with increased susceptibility to viral infections (see Candotti et al., this Perspective series, ref. 4).Stat4-and Stat6-deficient animals reveal a requirement for IL-12-or IL-4-mediated proliferation of T cells, respectively (see Decker et al., this series, ref. 5).The phenotypes of Stat5A and Stat5B individual knockouts reveal the importance of Stat5A in breast development and lactation and the importance of Stat5B in the development of sexually dimorphic patterns of gene expression within the liver.In addition to these phenotypes, Stat5A/5B double knockouts are abnormal in their T cell and B cell development.Because Stat3-deficient animals die early in embryogenesis, the role of this protein in a number of biological functions had to be determined in conditional knockouts.As discussed by Levy and Lee in this series (6), Stat3 is implicated in keratinocyte migration, T cell apoptosis, IL-10-mediated signaling in macrophages, and the induction of apoptosis in the involuting breast.Beyond these various roles in normal cellular and physiological processes, the Stat proteins are now known to participate in cellular transformation and oncogenesis.Here, I consider the evidence implicating these molecules, particularly Stats 1, 3, and 5, in tumor formation and progression.