The Signal Transducers and Activator of Transcription (STAT) protein regulates many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced survival of tumors. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
The seven mammalian STAT family members identified are: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. STAT1 homodimers are involved in type II interferon signalling, and binds to the GAS (Interferon-Gamma Activated Sequence) promoter to induce expression of ISG (Interferon Stimulated Genes). In type I interferon signalling, STAT1-STAT2 heterodimer combines with IRF9 (Interferon Response Factor) to form ISGF3 (Interferon Stimulated Gene Factor), which binds to the ISRE (Interferon Stimulated Response Element) promoter to induce ISG expression.
STAT proteins were originally described as latent cytoplasmic transcription factors that require phosphorylation for nuclear retention. The unphosphorylated STAT proteins shuttles between cytosol and the nucleus waiting for its activation signal. Once the activated transcription factors reaches the nucleus it binds to consensus DNA-recognition motif called gamma activated sites (GAS) in the promoter region of cytokine inducible genes and activates transcription of these genes.
Extracellular binding of cytokines? induces activation of the intracellular [Janus kinase (JAK)? Janus kinase] that phosphorylates a specific tyrosine residue in the STAT protein which promotes the dimerization of STAT monomers via their SH2 domain. The phosphorylated dimer is then actively transported in the nucleus via importin a/b and RanGDP complex. Once inside the nucleus the active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site (GAS) motif and activate transcription of these genes. The STAT protein can be dephosphorylated by nuclear phosphatasess which leads to inactivation of STAT and the transcription factor becomes transported out of the nucleus by exportin crm1/RanGTP.
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