BACKGROUND Signal transducers and activators of transcription (STATs) were first discovered in protein complexes bound to the promoters of interferon-inducible genes. Seven STATs have now been cloned: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. These transcription factors participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling.1 STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. The seven mammalian STATs bear a conserved tyrosine residue near the C-terminus that is phosphorylated by JAKs. This phosphotyrosine permits the dimerization of STATs through interaction with a conserved SH2 domain. Phosphorylated STATs enter the nucleus by a mechanism that is dependent on importin-5 (also called nucleoprotein interactor 1) and the Ran nuclear import pathway. Once in the nucleus, dimerized STATs bind specific regulatory sequences to activate or repress transcription of target genes. Thus the JAK/STAT cascade provides a direct mechanism to translate an extracellular signal into a transcriptional response.2 In addition, serine phosphorylation of STATs may be required for the maximal induction of Stat-mediated gene activation.3 STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFN signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in IFN signaling, development of the mammary gland, response to GH, and embriogenesis. This latter group of STATS plays an important role in controlling cell-cycle progression and apoptosis and thus contributes to oncogenesis.
Although an increased expression of STAT1 has been observed in many human neoplasias, this molecule can be considered a potential tumor suppressor.4 On the other hand, STAT3 and 5 are considered as oncogenes, since they bring about the activation of cyclin D1, c-Myc, and bcl-xl expression, and are involved in promoting cell-cycle progression, cellular transformation, and in preventing apoptosis.5
STAT5 can be activated in response to diverse cytokines, hormones, and growth factors. There exist two Stat5 genes (Stat5a and Stat5b) that encode proteins of 92 and 94 kDa that are 95% identical. Their function is emphasized by their crucial role in the development of the mammary gland and the hematopoietic system. Cytokine receptor-associated Janus kinases (JAKs) activate Stat5 by phosphorylating Stat5 on Tyr694 which occurs in a similar sequence context to Tyr701 of Stat1. Phosphorylation on Tyr694 induces Stat5 dimerization, nuclear translocation, and DNA binding. STAT5 regulates the expression of cytokine target genes by binding to gamma interferon-activated sequence (GAS) motifs. Transcriptional activation requires the contact of STAT5 to coactivators and components of the transcription machinery. In addition, cross-talk with other signaling pathways as well as secondary modifications of STAT5 have been described to affect transactivation function.6
1. Artavanis-Tsakonas S et al.: Science 284: 770-776, 1999.
2. Oswald F et al.: Mol. Cell. Biol. 21: 7761–74, 2001.
3. Laky K & Fowlkes BJ: Curr. Opin. Immunol. 20: 197-202, 2008.
4. Chen, S. & Schreiber, S.:Cancer Res. 69(24 Suppl):Abstract nr 65, 2009
5. Calò, V. et al: J. Cell. Physiol. 197:157-68, 2003
6. Groner, B. et al: Growth Horm IGF Res. 10(Suppl B):S15-20, 2000
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