STAT3 Function In Vivo

Abstract

STAT3 is perhaps the STAT family member whose physiological functions are less well understood. It was initially identified as Acute Phase Response Factor (APRF), a DNA-binding activity appearing in IL-6-treated hepatocytes and interacting with an Acute Phase Response Element (APRE) on the promoter of several IL-6-responsive genes (1). Molecular cloning identified then STAT3/APRF as the EGF-inducible factor binding to the sis-inducible element of the c-fos promoter (2–4). STAT3 can form both homo-and hetero-dimers with STAT1 and bind to sequences very similar to the GAS sites, the typical STAT1 recognition elements. STAT3 can be activated not only by all members of the IL-6 family of cytokines, which share gp130 as a receptor signalling subunit, but also by a great number of other cytokines including leptin, IL-12, Interferons, IL-10 and G-CSF as well as by growth factors and oncogenes (5). Indeed, aberrant STAT3 activity is found in a number of tumor cell lines and primary tumors, where it contributes to uncontrolled proliferation or abnormal survival (6). Unlike other STAT factors, whose inactivation by gene targeting revealed in most cases a good degree of functional specificity, targeted inactivation of the STAT3 gene added to the extreme complexity of its functions. Both in vitro and in vivo studies have shown that one of the peculiar characteristics of STAT3 is its capacity to activate different sets of genes in different cell types. This is probably achieved through specific interactions with different transcription factors in different cell and promoter contexts. In addition, STAT3 exists in two alternatively spliced forms, the full length STAT3α and the truncated STAT3β, which lacks the carboxi-terminal activation domain and was initially considered as a dominant negative form (7, 8). However, recent studies have suggested that this isoform can exert both negative and positive effects on transcription, thus further fogging the picture (9). It is likely that the final outcome of STAT3 activation in a specific cellular compartment will depend on the physiological/pathological context, which in turn will determine a specific cytokine/growth factor milieu and therefore coordinated activation of different factors including STAT3 (α and/or β). However, neither the specific contribution of STAT3 to several different cytokine pathways nor the nature and identity of the factors interacting with it are completely understood. Here we intend to summarize the sometimes apparently contrasting findings obtained through in vivo studies in an attempt to identify the main physiological and pathological functions of this multifaceted factor.