Scurfin (FOXP3) Acts as a Repressor of Transcription and Regulates T Cell Activation*

@article{Schubert2001ScurfinA,
  title={Scurfin (FOXP3) Acts as a Repressor of Transcription and Regulates T Cell Activation*},
  author={Lisa A. Schubert and Eric Jeffery and Yi Zhang and Fred Ramsdell and Steven F. Ziegler},
  journal={The Journal of Biological Chemistry},
  year={2001},
  volume={276},
  pages={37672 - 37679}
}
We have recently identified and clonedFoxp3, the gene defective in mice with thescurfy mutation. The immune dysregulation documented in these mice and in humans with mutations in the orthologous gene indicates that the foxp3 gene product, scurfin, is involved in the regulation of T cell activation and differentiation. The autoimmune state observed in these patients with the immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome, or X-linked autoimmunity-allergic dysregulation… 

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It is shown that FOXP3 interacts with retinoic acid receptor-related orphan receptor (ROR)α, and that this interaction inhibits transcriptional activation mediated by ROR α, and the inhibition of RORα does not require an intact forkhead domain, demonstrating a mode ofFOXP3 function that is independent of DNA binding.
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References

SHOWING 1-10 OF 46 REFERENCES
Suppression of T cell function: a potential role for transcriptional repressor ICER
TLDR
It is shown that the binding of ICER to CD28RE and/or composite motifs containing CRE‐like DNA motifs may lead to uncoupling of CBP/p300 thus extinguishing IL‐2 expression as well as expression of numerous other cytokines and chemokines.
Negative Regulation of the Forkhead Transcription Factor FKHR by Akt*
TLDR
FKHR may be a direct nuclear regulatory target for Akt in both metabolic and cell survival pathways, and mutation of these three sites to alanine residues enhances the transcriptional activity of FKHR and renders it resistant to inhibition by Akt.
Transcription factors of the NFAT family: regulation and function.
TLDR
Recent data on the diversity of the NFAT family of transcription factors, the regulation of NFAT proteins within cells, and the cooperation ofNFAT proteins with other transcription factors to regulate the expression of inducible genes are discussed.
The Human gp39 Promoter
TLDR
The results suggest that NF-ATp, via binding to at least two cis-elements, is essential for the induction of gp39 gene expression in response to T cell activation.
Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse
TLDR
Genetic complementation demonstrates that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis.
Cellular and molecular characterization of the scurfy mouse mutant.
TLDR
Flow cytometric analyses of lymphoid cell populations reveal that scurfy syndrome is characterized by changes in several phenotypic parameters, including an increase in Mac-1+ cells and a decrease in B220+ cells, changes that may result from the production of extremely high levels of the cytokine granulocyte-macrophage CSF by scurfi T cells.
The proximal promoter of the IL-4 gene is composed of multiple essential regulatory sites that bind at least two distinct factors.
TLDR
High-resolution mutagenesis of this 33-bp region revealed multiple sites indispensable for inducible IL-4 transcription, including overlapping binding sites for the cyclosporin A-sensitive factor NF-ATp and a novel constitutively expressed factor designated PCC.
JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome.
TLDR
The results point to a critical role for JM2 in self tolerance and Th cell differentiation, and one point mutation at a splice junction site results in transcripts that encode a truncated protein lacking the fork head homology domain.
Role of the forkhead transcription family member, FKHR, in thymocyte differentiation
TLDR
It is demonstrated that FKHR is expressed in thymocytes, most prominently in those that are undergoing positive selection, and data suggest that the transcription factor may be involved in cell survival and/or cycling.
Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes
TLDR
Overall, the phenotypic characteristics of scurfy disease correlated well with increased interleukin (IL)‐4 (lymphadenopathy), IL‐6 (B cell proliferation, hypergammaglobulinemia, IL‐7 (dermal inflammatory cell infiltration), and high levels of tumor necrosis factor‐α (wasting).
...
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