STATs as critical mediators of signal transduction and transcription: lessons learned from STAT5.
Signal transducers and activators of transcription (Stats) comprise a family of seven transcription factors that are activated by a variety of cytokines, hormones and growth factors. Stats are activated through tyrosine phosphorylation, mainly by Jak kinases, that lead to their dimerization, nuclear translocation and regulation of target gene expression. Stat5 was originally identified as a transcription factor that regulates the beta-casein gene in response to prolactin (PRL), but Stat5 is activated also by several other cytokines and growth factors. The molecular mechanisms that underlie Stat5-mediated transcription involve interactions and cooperation with sequence specific transcription factors and transcriptional coregulators. Our studies identified p100 protein as a coactivator for Stat5, and suggest the existence of a positive regulatory loop in PRL-induced transcription, where PRL stabilizes p100 protein, which in turn can cooperate with Stat5 in transcriptional activation. Suppressors of cytokine signaling (SOCS) proteins are important negative regulators of Stats. A target gene for Stat5, the serine/threonine kinase Pim-1, was found to cooperate with SOCS-1 and SOCS-3 to inhibit Stat5 activity suggesting that Pim-1 together with SOCS-1 and SOCS-3 are components of a negative feedback mechanism that allows Stat5 to regulate its own activation.
Paukku
Kirsi
K
Department of Virology, Haartman Institute and Biomedicum Helsinki, University of Helsinki, PO Box 63, FIN-00014 Helsinki, Finland. kpaukku@mappi.helsinki.fi
Silvennoinen
Olli
O
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000378:metabolism; D008894:Milk Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1; D011956:Receptors, Cell Surface / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D016207:Cytokines; D004268:DNA-Binding Proteins; D006133:Growth Substances; D008894:Milk Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D019204:GTP-Binding Proteins