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Stat5b  -  signal transducer and activator of...

Mus musculus

Synonyms: Signal transducer and activator of transcription 5B
 
 
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Disease relevance of Stat5b

  • 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].
  • However, ectopic expression of the Y845F-EGFR prevented the EGF from protecting MDA-MB-231 breast cancer cells from adriamycin-induced apoptosis, whereas two mutants of Stat5b, a dominant-interfering mutant (DNstat5b) and a tyrosine mutation at 699 (Y699F-Stat5b) did not [2].
  • In tissues from 33 individuals with head and neck cancer, Stat5 activation levels were correlated with progression to a malignant phenotype, where increased expression and phosphorylation of Stat5b were detected consistently in tumors compared with their epithelial counterparts [3].
  • Thus, ERalpha appears to play a key role in the mechanism that inhibits nuclear localization of Stat5b in female mice, leading to feminization of a ERalpha-GH-Stat5b pathway and Cyp expression [4].
  • Acceleration of Stat5b transgene-mediated lymphoma occurred on TCRalpha(-/-) and pre-TCRalpha(-/-) backgrounds [5].
 

High impact information on Stat5b

  • Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses [6].
  • Similar to the defect in proliferation in activated splenocytes, freshly isolated splenocytes from Stat5b-/- mice exhibited greatly diminished proliferation in response to IL-2 and IL-15 [7].
  • Stat5b also induced basal transcription in the absence of PRL [8].
  • Finally, we found that eosinophilopoiesis induced by the administration of recombinant IL-5 was also diminished in Stat5a(-/-) mice and Stat5b(-/-) mice [9].
  • Lactogenic hormone treatment of HC11 mammary cells resulted in tyrosine phosphorylation of Stat5a and Stat5b, dimerization, and rapid nuclear translocation of both Stat5 proteins [10].
 

Biological context of Stat5b

 

Anatomical context of Stat5b

  • Using mouse embryonic fibroblasts with targeted disruption of the Stat5a and Stat5b genes, we demonstrate that full activation of Stat5 is required for Type I interferon-dependent gene transcription via GAS elements [15].
  • Our findings with dnStat5-expressing chicken myeloblasts were confirmed with primary hematopoietic cells from Stat5a/Stat5b-deficient mice [16].
  • Expression levels of CD38-induced germline gamma1 transcripts and AID in Stat5a(-/-) and Stat5b(-/-) B cells upon IL-5 stimulation were comparable to those of wild-type B cells [13].
  • 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 [17].
  • We demonstrated that refeeding of fasted mice leads to rapid activation of Stat5 proteins in liver, skeletal muscle, and fat, suggesting that Stat5b is a physiological target of insulin [18].
 

Associations of Stat5b with chemical compounds

  • In female mice, however, disruption of either Stat5a or Stat5b led to striking decreases in several liver CYP-catalyzed testosterone hydroxylase activities [19].
  • Our sequencing analysis revealed a unique mutation C1462A that results in a leucine to methionine (L327M) in Stat5b of NOD mice [20].
  • Here, we show that injection of glucose or insulin into fasted mice leads to robust activation of both Stat5a and Stat5b in skeletal muscle [18].
  • Differences in serine phosphorylation(s) of Stat5a and Stat5b, or Stat5 associations with adaptor proteins or co-transcription factors are other potential sources of functional disparity and the signal amplitude, frequency or duration also can be significant [21].
  • We conclude that ERalpha and ERbeta act as coactivators for Stat5b through a mechanism which is independent of AF-1 and AF-2 [22].
 

Physical interactions of Stat5b

 

Other interactions of Stat5b

  • Both the expression of Crkl and the Stat5b binding ability are the highest in B6.NOD-c11 and the lowest in NOD while intermediate in B6 and NOD.Lc11 mice [24].
  • We report here a defective gene (Stat5b) located on chromosome 11 within a previously mapped T1D susceptibility interval (Idd4) in the nonobese diabetic (NOD) mice [20].
  • The inapt transcriptional regulation ability of the mutated Stat5b is proved by decreased levels of RNA of Stat5b-regulated genes (IL-2Rbeta and Pim1) [20].
  • Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells [22].
  • MATERIALS AND METHODS: Delta60-Mpl knockin mice, Stat5a(-/-)/b(-/-), Stat5a(-/-), and Stat5b(-/-) mice and wild-type (WT) controls were given a lethal myelosuppressive regimen: 80 mg/kg carboplatin intravenously followed by 7.5 or 6.5 Gy 137Cs total-body irradiation [25].
 

Analytical, diagnostic and therapeutic context of Stat5b

References

  1. Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma. Kelly, J.A., Spolski, R., Kovanen, P.E., Suzuki, T., Bollenbacher, J., Pise-Masison, C.A., Radonovich, M.F., Lee, S., Jenkins, N.A., Copeland, N.G., Morse, H.C., Leonard, W.J. J. Exp. Med. (2003) [Pubmed]
  2. Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Boerner, J.L., Demory, M.L., Silva, C., Parsons, S.J. Mol. Cell. Biol. (2004) [Pubmed]
  3. Constitutive activation of Stat5b contributes to carcinogenesis in vivo. Xi, S., Zhang, Q., Gooding, W.E., Smithgall, T.E., Grandis, J.R. Cancer Res. (2003) [Pubmed]
  4. Developmental action of estrogen receptor-alpha feminizes the growth hormone-Stat5b pathway and expression of Cyp2a4 and Cyp2d9 genes in mouse liver. Sueyoshi, T., Yokomori, N., Korach, K.S., Negishi, M. Mol. Pharmacol. (1999) [Pubmed]
  5. A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling. Bessette, K., Lang, M.L., Fava, R.A., Grundy, M., Heinen, J., Horne, L., Spolski, R., Al-Shami, A., Morse, H.C., Leonard, W.J., Kelly, J.A. Blood (2008) [Pubmed]
  6. Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Teglund, S., McKay, C., Schuetz, E., van Deursen, J.M., Stravopodis, D., Wang, D., Brown, M., Bodner, S., Grosveld, G., Ihle, J.N. Cell (1998) [Pubmed]
  7. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. Imada, K., Bloom, E.T., Nakajima, H., Horvath-Arcidiacono, J.A., Udy, G.B., Davey, H.W., Leonard, W.J. J. Exp. Med. (1998) [Pubmed]
  8. Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Liu, X., Robinson, G.W., Gouilleux, F., Groner, B., Hennighausen, L. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  9. Both stat5a and stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue. Kagami, S., Nakajima, H., Kumano, K., Suzuki, K., Suto, A., Imada, K., Davey, H.W., Saito, Y., Takatsu, K., Leonard, W.J., Iwamoto, I. Blood (2000) [Pubmed]
  10. Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocortiocoid receptor in mammary cells. Cella, N., Groner, B., Hynes, N.E. Mol. Cell. Biol. (1998) [Pubmed]
  11. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Moriggl, R., Topham, D.J., Teglund, S., Sexl, V., McKay, C., Wang, D., Hoffmeyer, A., van Deursen, J., Sangster, M.Y., Bunting, K.D., Grosveld, G.C., Ihle, J.N. Immunity (1999) [Pubmed]
  12. Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Moriggl, R., Sexl, V., Piekorz, R., Topham, D., Ihle, J.N. Immunity (1999) [Pubmed]
  13. Essential role of Stat5 for IL-5-dependent IgH switch recombination in mouse B cells. Horikawa, K., Kaku, H., Nakajima, H., Davey, H.W., Hennighausen, L., Iwamoto, I., Yasue, T., Kariyone, A., Takatsu, K. J. Immunol. (2001) [Pubmed]
  14. STAT family of transcription factors in cytokine-mediated biological responses. Takeda, K., Akira, S. Cytokine Growth Factor Rev. (2000) [Pubmed]
  15. Role of Stat5 in type I interferon-signaling and transcriptional regulation. Uddin, S., Lekmine, F., Sassano, A., Rui, H., Fish, E.N., Platanias, L.C. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  16. Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation. Kieslinger, M., Woldman, I., Moriggl, R., Hofmann, J., Marine, J.C., Ihle, J.N., Beug, H., Decker, T. Genes Dev. (2000) [Pubmed]
  17. Stat5a is mandatory for adult mammary gland development and lactogenesis. Liu, X., Robinson, G.W., Wagner, K.U., Garrett, L., Wynshaw-Boris, A., Hennighausen, L. Genes Dev. (1997) [Pubmed]
  18. Insulin Induction of SOCS-2 and SOCS-3 mRNA expression in C2C12 Skeletal Muscle Cells Is Mediated by Stat5*. Sadowski, C.L., Choi, T.S., Le, M., Wheeler, T.T., Wang, L.H., Sadowski, H.B. J. Biol. Chem. (2001) [Pubmed]
  19. Distinctive roles of STAT5a and STAT5b in sexual dimorphism of hepatic P450 gene expression. Impact of STAT5a gene disruption. Park, S.H., Liu, X., Hennighausen, L., Davey, H.W., Waxman, D.J. J. Biol. Chem. (1999) [Pubmed]
  20. A mutant Stat5b with weaker DNA binding affinity defines a key defective pathway in nonobese diabetic mice. Davoodi-Semiromi, A., Laloraya, M., Kumar, G.P., Purohit, S., Jha, R.K., She, J.X. J. Biol. Chem. (2004) [Pubmed]
  21. Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Grimley, P.M., Dong, F., Rui, H. Cytokine Growth Factor Rev. (1999) [Pubmed]
  22. Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells. Björnström, L., Kilic, E., Norman, M., Parker, M.G., Sjöberg, M. J. Mol. Endocrinol. (2001) [Pubmed]
  23. Deletion of the carboxyl-terminal transactivation domain of MGF-Stat5 results in sustained DNA binding and a dominant negative phenotype. Moriggl, R., Gouilleux-Gruart, V., Jähne, R., Berchtold, S., Gartmann, C., Liu, X., Hennighausen, L., Sotiropoulos, A., Groner, B., Gouilleux, F. Mol. Cell. Biol. (1996) [Pubmed]
  24. Impaired Crkl expression contributes to the defective DNA binding of Stat5b in nonobese diabetic mice. Laloraya, M., Davoodi-Semiromi, A., Kumar, G.P., McDuffie, M., She, J.X. Diabetes (2006) [Pubmed]
  25. Differential role of Stat5 isoforms in effecting hematopoietic recovery induced by Mpl-ligand in lethally myelosuppressed mice. Pestina, T.I., Jackson, C.W. Exp. Hematol. (2003) [Pubmed]
  26. Regulation of progesterone levels during pregnancy and parturition by signal transducer and activator of transcription 5 and 20alpha-hydroxysteroid dehydrogenase. Piekorz, R.P., Gingras, S., Hoffmeyer, A., Ihle, J.N., Weinstein, Y. Mol. Endocrinol. (2005) [Pubmed]
 
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