Specific Inhibition of Stat5a/b Promotes Apoptosis of IL-2-Responsive Primary and Tumor-Derived Lymphoid Cells 1

@article{Behbod2003SpecificIO,
  title={Specific Inhibition of Stat5a/b Promotes Apoptosis of IL-2-Responsive Primary and Tumor-Derived Lymphoid Cells 1},
  author={Fariba Behbod and Zsuzsanna S. Nagy and Stanislaw M. Stepkowski and James G. Karras and Charlene R. Johnson and W. David Jarvis and Robert A. Kirken},
  journal={The Journal of Immunology},
  year={2003},
  volume={171},
  pages={3919 - 3927}
}
Stat5a/b exhibits 96% homology and are required for normal immune function. The present studies examined Stat5a/b function in lymphoid cells by specific and simultaneous disruption of both proteins using novel phosphorothioate-2′-O-methoxyethyl antisense oligodeoxynucleotides (asODN). Efficient delivery was confirmed by the presence of fluorescent TAMRA-labeled ODN in ≥55 and 95% in human primary and tumor cell lines, respectively. Acute asODN administration reduced levels of Stat5a (90%) in 6… 

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References

SHOWING 1-10 OF 67 REFERENCES
Immunocompromised tumor-bearing mice show a selective loss of STAT5a/b expression in T and B lymphocytes.
TLDR
The correlation in the loss of T and B cell function with the selective decrease in STAT5a/b expression suggests that regulation of the STAT5 signaling pathway may provide a molecular mechanism for modulating the immune system.
Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation.
TLDR
The findings suggest that Stat5 may promote cytokine-dependent survival and proliferation of differentiating myeloid progenitor cells in stress or pathological situations, such as inflammation.
Concomitant Inhibition of Janus Kinase 3 and Calcineurin-Dependent Signaling Pathways Synergistically Prolongs the Survival of Rat Heart Allografts1
TLDR
It is reported that AG-490 significantly prolonged allograft survival, but also acted synergistically when used in combination with the signal 1 inhibitor cyclosporin A, but not the signal 3 inhibitor, rapamycin.
The IL-2 Receptor Promotes Lymphocyte Proliferation and Induction of the c-myc, bcl-2, and bcl-x Genes Through the trans-Activation Domain of Stat51
TLDR
Stat5 is a critical component of the proliferative signal from Tyr510 of the IL-2R and regulates expression of both mitogenic and survival genes through its trans-activation domain.
Erythropoietin Can Induce the Expression of Bcl-xLthrough Stat5 in Erythropoietin-dependent Progenitor Cell Lines*
TLDR
Eo-dependent activation of Stat5 is a transcriptional pathway that can be used by Epo-responsive progenitor cells to induce the expression of bcl-xL and consequently to inhibit apoptosis.
Suppression of STAT5 Functions in Liver, Mammary Glands, and T Cells in Cytokine-Inducible SH2-Containing Protein 1 Transgenic Mice
TLDR
The cloned CIS1-dependent immediate-early cytokine-responsive gene, CIS1, functions as a specific negative regulator of STAT5 in vivo and plays an important regulatory role in the liver, mammary glands and T cells.
Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells.
Interferon-alpha inhibits Stat5 DNA-binding in IL-2 stimulated primary T-lymphocytes.
TLDR
The results provide a possible molecular link between the prominent antiproliferative effects of IFN-alpha on IL-2 induced T-cell proliferation and the signal transduction pathways emerging from the IL- 2 receptor.
Shp-2 Tyrosine Phosphatase Functions as a Negative Regulator of the Interferon-Stimulated Jak/STAT Pathway
TLDR
It is proposed that Shp-2 acts to promote cell growth and survival through two mechanisms, i.e., the stimulation of growth factor-initiated mitogenic pathways and the suppression of cytotoxic effect elicited by cytokines, such as IFNs.
...
...