The role of STATs in transcriptional control and their impact on cellular function

The STAT proteins (Signal Transducers and Activators of Transcription), mer e identified in the last decade as transcription factors which were critica l in mediating virtually all cytokine driven signaling, These proteins are latent in the cytoplasm and become activated through tyrosine phosphorylati on which typically occurs through cytokine receptor associated kinases (JAK s) or growth factor receptor tyrosine kinases, Recently a number of non-rec eptor tyrosine kinases (for example src and abl) have been found to cause S TAT phosphorylation, Phosphorylated STATs form homo- or hetero-dimers, ente r the nucleus and working coordinately with other transcriptional co-activa tors or transcription factors lead to increased transcriptional initiation. In normal cells and in animals, ligand dependent activation of the STATs i s a transient process, lasting for several minutes to several hours. In con trast, in many cancerous cell lines and tumors, where growth factor dysregu lation is frequently at the heart of cellular transformation, the STAT prot eins (in particular Stats 1, 3 and 5) are persistently tyrosine phosphoryla ted or activated. The importance of STAT activation to growth control in ex periments using anti-sense molecules or dominant negative STAT protein enco ding constructs performed in cell lines or studies in animals lacking speci fic STATs strongly indicate that STATs play an important role in controllin g cell cycle progression and apoptosis, Stat1 plays an important role in gr owth arrest, in promoting apoptosis and is implicated as a tumor suppressor : while Stats 3 and 5 are involved in promoting cell cycle progression and cellular transformation and preventing apoptosis, Many questions remain inc luding: (I) a better understanding of how the STAT proteins through associa tion with other factors increase transcription initiation; (2) a more compl ete definition of the sets of genes which are activated by different STATs and (3) how these sets of activated genes differ as a function of cell type . Finally, in the context of many cancers, where STATs are frequently persi stently activated, an understanding of the mechanisms leading to their cons titutive activation and defining the potential importance of persistent STA T activation in human tumorigenesis remains.