STAT nuclear translocation: potential for pharmacological intervention

The signal transducer and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate broadly diverse biological processes, including cell proliferation, transformation, apoptosis, differentiation, fetal development, inflammation and immune response. Stimulation with multiple cytokines or growth factors all result in the tyrosine phosphorylation of STAT proteins and the subsequent gene regulation via their direct binding to the promoters of responsive genes. Cytokine-regulated gene activation is dependent on the continuous nucleocytoplasmic cycling of STAT signal transducers. The STATs use intricately intertwined karyopherin-dependent and -independent translocation mechanisms to coordinate the activation step at the cell membrane and gene expression in the nucleus. In addition, STATs appear to have cytokine-independent gene regulatory functions that may also depend on their regulated nucleocytoplasmic transfer. Numerous studies have implicated aberrant STAT signalling in cancer, immune defects and inflammatory diseases. Given the central role of intracellular trafficking for the proper signal processing by STAT proteins, pharmacological targeting of STAT nucleocytoplasmic translocation appears to be an attractive strategy to interfere with dysregulated cytokine signalling. This review will discuss possible scenarios that would result from the use of novel modulators of STAT shuttling, which may both increase or decrease STAT activation and, hence, transcriptional activity.