Disease relevance of Stat5a

• We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment [1].
• We analyzed the role of Stat5a/b isoforms in squamous cell carcinoma of the head and neck using expression and activation studies in human tissues and in a xenograft model after selective targeting [2].
• Decreasing Stat5a activation levels could be a therapeutic approach for reducing survival of breast cancer cells [3].
• Similar to human breast cancers, a proportion of mammary adenocarcinomas in the WAP-TAg transgenic mouse model demonstrate constitutive Stat5a/b and Stat3 activation [3].
• These features were reminiscent of acinar cyst formation and degeneration frequently observed in human benign prostate hyperplasia, however, cystic changes in prostate acini of Stat5a-deficient mice were not associated with increased prostate size or morphologic hallmarks of epithelial hyperplasia [4].

Psychiatry related information on Stat5a

• Mammary-directed expression of the wild-type Stat5, constitutively activated Stat5 and carboxyl-terminally truncated dominant negative Stat5 forms resulted in mammary tumors with incidence rates of up to 22% and latency periods of 8-12 months [5].

High impact information on Stat5a

• Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction [6].
• Stat5 is rapidly activated following EpoR stimulation, but its function in erythropoiesis has been unclear since adult Stat5a-/-5b-/- mice have normal steady-state hematocrit [6].
• Here we show that Stat5 is essential for the high erythropoietic rate during fetal development [6].
• Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses [7].
• 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 [7].

Chemical compound and disease context of Stat5a

• Stat5a was nuclear localized and tyrosine phosphorylated in 59 of 78 (76%) breast cancers examined; 38 of 78 (49%) demonstrated Stat5a nuclear localization in more than 25% of the breast cancer cells within the adenocarcinomas [8].
• Activation of the JAK1-STAT5 pathway by binding of the Friend virus gp55 glycoprotein to the erythropoietin receptor [9].

Biological context of Stat5a

• The activity pattern of two STAT proteins, Stat5a and Stat5b, in mammary tissue during pregnancy suggests an active role for these transcription factors in epithelial cell differentiation and milk protein gene expression [10].
• These phenotypes are not seen in mice lacking Stat5a or Stat5b alone [11].
• Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression [11].
• Mammary glands expressing inactive Pak1 exhibited a reduction of Stat5a Ser 779 phosphorylation [12].
• Most strikingly, Stat5a/b(null/null) cells were resistant to transformation and leukemia development induced by Abelson oncogenes, whereas Stat5a/b(DeltaN/DeltaN)-derived cells readily transformed [13].

Anatomical context of Stat5a

• Stat5a is mandatory for adult mammary gland development and lactogenesis [10].
• Our findings with dnStat5-expressing chicken myeloblasts were confirmed with primary hematopoietic cells from Stat5a/Stat5b-deficient mice [14].
• We have now analyzed the immune system of Stat5a-deficient mice [15].
• Furthermore, myeloproliferative disease was induced by reconstitution with bone marrow cells expressing a constitutively active mutant, Stat5a, or a single Stat5a target, murine oncostatin M (mOSM) [16].
• Stat5a regulates T helper cell differentiation by several distinct mechanisms [17].

Associations of Stat5a with chemical compounds

• Although activated by IL-7, Stat5a/b (Stat, signal transducer and activator of transcription) have been thought to play limited roles in lymphoid development [18].
• In C2C12 myotubes, we find that insulin stimulates tyrosine phosphorylation of Stat5a and Stat5b by 3-5-fold [19].
• Here, we show that injection of glucose or insulin into fasted mice leads to robust activation of both Stat5a and Stat5b in skeletal muscle [19].
• In female mice, however, disruption of either Stat5a or Stat5b led to striking decreases in several liver CYP-catalyzed testosterone hydroxylase activities [20].
• These results define a negative cross talk between PR and Stat5a/GR that may contribute to the physiological role of progesterone to repress lactogenic hormone induction of the beta-casein gene in the mammary gland during pregnancy [21].
• GH effectively protected Stat5(+/+) cells against glutamate toxicity but had no effect in Stat5(-/-) neurons or in Stat5(+/+) neurons treated with JAK2/Stat or PI3K inhibitor [22].

Physical interactions of Stat5a

• IL-2 induced the binding of Stat5a and b proteins to the human GASd element [23].
• Furthermore, chromatin immunoprecipitation assays revealed that Stat5a binds to the SOCS3 promoter in CD4(+) T cells [24].
• In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein [25].
• EMSA analysis using a Stat 5 binding site showed both PRLs to cause equivalent binding of nuclear proteins and that most of what bound was complexed through Stat 5a [26].
• However, following prolactin induction the Ser(725) mutant displayed sustained DNA binding activity compared with that of wild type Stat5a [27].

Enzymatic interactions of Stat5a

• In turn, JAK2 phosphorylates and activates STAT5, a member of the signal transducers and activators of transcription (STAT) family [28].
• In addition, Lyn was demonstrated to phosphorylate the EpoR and Stat5 on tyrosines in vitro [29].
• We have previously shown that in HC11 mammary epithelial cells Stat5a is phosphorylated on Tyr(694) in a prolactin-sensitive manner, whereas serine phosphorylation is constitutive (Wartmann, M., Cella, N., Hofer, P., Groner, B., Xiuwen, L., Hennighausen, L., and Hynes, N. E. (1996) J. Biol. Chem. 271, 31863-31868) [27].
• A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the docking model of STAT activation [30].
• Our results suggest that STAT5 phosphorylated by IL-7 can directly up-regulate Pax5 transcription in early B cells [31].

Regulatory relationships of Stat5a

• Further analysis of the underlying mechanisms revealed that Pak1 stimulated beta-casein promoter activity in normal mouse mammary epithelial cells and also cooperated with Stat5a [12].
• Erythropoietin induces sustained phosphorylation of STAT5 in primitive but not definitive erythrocytes generated from mouse embryonic stem cells [32].
• These studies indicate that the IL-3 family of ligands is able to activate multiple isoforms of the signal transducing protein Stat5 [33].
• These data suggest that the presence of STAT5A during the GM-CSF-induced assembly of STAT5 dimers is critical for the formation of competent transcription factors that are required for both gene expression and cell proliferation [34].
• Nuclear factor I and mammary gland factor (STAT5) play a critical role in regulating rat whey acidic protein gene expression in transgenic mice [35].

Other interactions of Stat5a

• Correspondingly, we show that Stat5a is essential for maximal responsiveness to antigenic stimuli in vivo, underscoring the physiological importance of IL-2-induced IL-2R alpha expression [15].
• The increase of Stat5 expression during pregnancy coincides with the activation of the WAP gene [36].
• A comparative analysis of Jak2-deficient mammary glands with transplants from Stat5a/b knockouts revealed that Jak2 deficiency also impairs the pregnancy-induced branching morphogenesis [37].
• Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7 [38].
• However, it is the relative importance and redundancy of Stat6 and Stat5a in Th2 cell differentiation and allergic airway inflammation are unknown [39].
• In vitro kinase assays revealed that STAT5 is a direct target of Flt3 [40].

Analytical, diagnostic and therapeutic context of Stat5a

• To investigate the function of Stat5a in mammopoiesis and lactogenesis we disrupted this gene in mice by gene targeting [10].
• In addition, immunodepletion experiments followed by gel shift analyses revealed the presence of active Stat5a and Stat5b homodimers [41].
• Immunoprecipitation experiments revealed that in mammary cells, Stat5a, Stat5b, and the GR are physically associated in vivo [41].
• Only Stat5a transfection increased the expression of adipogenic markers peroxisome proliferator-activated receptor gamma, CCAAT enhancer binding protein (C/EBP)alpha, and adipose protein 2/fatty acid-binding protein in response to GH, as determined by quantitative RT-PCR [42].
• Instead, immunohistochemistry of the prostate-specific secretory marker, probasin, suggested that hypersecretory function of the epithelium could underlie local congestion and cyst formation in prostates of Stat5a-null mice [4].

References