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

• These phenotypes are not seen in mice lacking Stat5a or Stat5b alone [11].
• Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue [8].
• Mice deficient in Stat5a and Stat5b have demonstrated the essential role that these highly related proteins play in cell cycle progression following peripheral T cell activation [12].
• Stat5a(-/-) and Stat5b(-/-) B cells showed similar cell division cycles, but they did not undergo mu-gamma1 CSR [13].
• Analyses of Stat5a and Stat5b knockout mice reveal important roles in prolactin-mediated mammary gland development and growth hormone-mediated induction of sexual dimorphism, respectively [14].

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

• We propose that Stat5a delta 750 and Stat5b delta 754 are lacking functional transactivation domains and exert their dominant negative effects by blocking the DNA-binding site in Stat5-responsive gene promoters [23].
• Impaired Crkl expression contributes to the defective DNA binding of Stat5b in nonobese diabetic mice [24].

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

• In addition, immunodepletion experiments followed by gel shift analyses revealed the presence of active Stat5a and Stat5b homodimers [10].
• Immunoprecipitation experiments revealed that in mammary cells, Stat5a, Stat5b, and the GR are physically associated in vivo [10].
• The two highly related signal transducers and activators of transcription (Stats), Stat5a and Stat5b, are major mediators of prolactin signaling in both the mammary gland and in the ovary [26].
• In a xenograft model, blockade of Stat5b, but not Stat5a, using antisense oligonucleotides resulted in tumor growth inhibition and abrogation of Stat5 target genes in vivo [3].

References