STATs are proteins that serve the dual function of signal transducers and activators of transcription in cells exposed to signaling polypeptides. A variety of cytokines mediate the activation of Janus protein tyrosine kinases (Jaks). The Jaks then phosphorylate cellular substrates, including members of the signal transducers and activators of transcription (Stat) family of transcription factors. Lin et al. (1996) isolated a second human Stat5 cDNA, Stat5B, and demonstrated that the genes encoding both Stat5A and Stat5B are located at chromosome 17q11.2.
NCBI Summary:
The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein mediates the signal transduction triggered by various cell ligands, such as IL2, IL4, CSF1, and different growth hormones. It has been shown to be involved in diverse biological processes, such as TCR signaling, apoptosis, adult mammary gland development, and sexual dimorphism of liver gene expression. This gene was found to fuse to retinoic acid receptor-alpha (RARA) gene in a small subset of acute promyelocytic leukemias (APLL). The dysregulation of the signaling pathways mediated by this protein may be the cause of the APLL.
General function
Intracellular signaling cascade, Nucleic acid binding, DNA binding, Transcription factor
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Cellular localization
Nuclear
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Ovarian function
Luteinization
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Alpha2-macroglobulin (alpha2M) is a serine protease inhibitor and cytokine inactivator associated with inflammation and tissue remodeling. The gene encoding this protein is selectively induced in the rat corpus luteum by the luteotropic hormone and cytokine, PRL. Dajee et al reported that the promoter of the alpha2M gene contains two regulatory regions that bind a diverse set of transcription factors and confer functional activity in ovarian granulosa-luteal cells. The PRL response element (PRLRE) binds PRL-activated (tyrosine-phosphorylated) signal transducers and activators of transcription (Stat 5b and Stat 5a). Cotransfection with a vector expressing a dominant negative, truncated form of Stat 5b abolished PRL-induced activation of a2M transgenes. 5'-Deletion of the Stat-binding sites abolished all promoter-reporter activity in response to PRL Dajee et al. (1998).
Expression regulated by
LH, Growth Factors/ cytokines, prolactin
Comment
Carvalho CR, et al reported a novel signal transduction pathway for luteinizing hormone and its interaction with insulin and the activation of Janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/Akt pathways.
The actions of LH are mediated through a single class of cell surface LH/human chorionic gonadotropin receptor, which is a member of the G protein-coupled receptor family. In the present study the authors showed that LH induced rapid tyrosine phosphorylation and activation of the Janus kinase 2 (JAK2) in rat ovary. Upon JAK2 activation, tyrosine phosphorylation of signal transducer and activator of transcription-1 (STAT-1), STAT-5b, insulin receptor substrate-1 (IRS-1), and Src homology and collagen homology (Shc) were detected. In addition, LH induced IRS-1/phosphoinositol 3-kinase and Shc /growth factor receptor-binding protein 2 (Grb2) associations and downstream AKT (protein kinase B, homologous to v-AKT) serine phosphorylation and ERK tyrosine phosphorylation, respectively. The simultaneous infusion of insulin and LH induced higher phosphorylation levels of JAK2, STAT5b, IRS-1, and AKT compared with each hormone alone in the whole ovary of normal rats. By immunohistochemistry the authors demonstrated that these late events take place in follicular cells and both external and internal theca. These results indicate a new signal transduction pathway for LH and show that there is positive cross-talk between the insulin and LH signaling pathways at the level of phosphoinositol 3-kinase/AKT pathway in this tissue.
Ovarian localization
Luteal cells
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Follicle stages
Corpus luteum
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: unknown Comment: Among the Stats, the two highly related proteins, Stat5a and Stat5b, are activated by a variety of cytokines. Teglund et al. (1998) studied the role of the Stat5 proteins by generating mutant mice that have the genes deleted individually or together. The phenotypes of the mice demonstrate an essential, and often redundant, role for the two Stat5 proteins in a spectrum of physiological responses associated with growth hormone and prolactin. Conversely, the responses to a variety of cytokines that activate the Stat5 proteins, including erythropoietin, are largely unaffected. Socolovsky et al. (1999) show that Stat5 is essential for the high erythropoietic rate during fetal development. Stat5a-/-5b-/- embryos are severely anemic; erythroid progenitors are present in low numbers, show higher levels of apoptosis, and are less responsive to Epo. These findings are explained by a crucial role for Stat5 in EpoR's antiapoptotic signaling: it mediates the immediate-early induction of Bcl-X(L) in erythroid cells through direct binding to the Bcl-X promoter.