Cytohesin Binder and Regulator Augments T Cell Receptor-induced Nuclear Factor of Activated T Cells·AP-1 Activation through Regulation of the JNK Pathway

Chen, Qian; Coffey, A.; Bourgoin, Sylvain G.; Gadina, Massimo

doi:10.1074/jbc.m601629200

Cited by 13 publications

(11 citation statements)

References 45 publications

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“…Among the VHL-HIF-dependent genes associated with metastasis in our model systems, CXCR4 and CXCR7 are G protein-coupled receptors for the chemokine CXCL12 1,17,18 . CYTIP is a ~40kDa intracellular protein that can enhance NFAT/AP1 transcriptional responses 31 , modulate cell adhesion and migration 32–34 , and support stem cell fitness 32 . LTBP1 is a large extracellular protein that regulates TGF-β activation 35 .…”

Section: Resultsmentioning

confidence: 99%

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer

Vanharanta

Shu

Brenet

et al. 2012

Nat Med

183

180

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Inactivation of the von Hippel-Lindau tumor suppressor (VHL) is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC), leading to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that liberation from PRC2-dependent repressive histone methylation (H3K27me3) activates HIF-driven CXCR4 expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven CYTIP expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.

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Section: Resultsmentioning

confidence: 99%

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer

Vanharanta

Shu

Brenet

et al. 2012

Nat Med

183

180

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“…DGKZ-deficient mice show enhanced upregulation of activation markers upon TCR engagement in both mature T cells and thymocytes (100). Finally, CYBR is a positive modulator of TCR signaling, enhancing the TCR-mediated activation of JNK/p38 MAP kinase activity by modulating the activity of the guanine nucleotide exchange factor VAV (12).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes

Kasler

Verdin

2007

Molecular and Cellular Biology

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Histone deacetylase 7 (HDAC7) is highly expressed in CD4 ؉ /CD8؉ thymocytes and functions as a signaldependent repressor of gene transcription during T-cell development. In this study, we expressed HDAC7 mutant proteins in a T-cell line and use DNA microarrays to identify transcriptional targets of HDAC7 in T cells. The changes in gene expression levels were compared to differential gene expression profiles associated with positive and negative thymic selection. This analysis reveals that HDAC7 regulates an extensive set of genes that are differentially expressed during both positive and negative thymic selection. Many of these genes play important functional roles in thymic selection, primarily via modulating the coupling between antigen receptor engagement and downstream signaling events. Consistent with the model that HDAC7 may play an important role in both positive and negative thymic selection, the expression of distinct HDAC7 mutants or the abrogation of HDAC7 expression can either enhance or inhibit the signal-dependent differentiation of a CD4 ؉ /CD8؉ cell line.The thymic development of T cells is a highly regulated process involving multiple extracellular signals. A complex integration of these signals results in changes in gene expression that can lead to the adoption of different developmental fates. Thymocytes pass two main developmental checkpoints that involve antigen receptor signaling. The first, called ␤-selection, occurs after the first of the two chains of the T-cell receptor (TCR) has been productively rearranged and is required for further developmental progression of thymocytes (24,55,75). After ␤-selection, thymocytes proliferate extensively, rearrange their antigen receptor ␣-chains, and become CD4 ϩ , CD8 ϩ , or double-positive (DP) thymocytes. The subsequent developmental fate of DP thymocytes is determined by signaling interactions with antigen-presenting cells (APCs) in the thymic cortex and medulla, most critically between the TCRs of thymocytes and self peptides bound to the major histocompatibility complex (MHC) molecules of the APCs. Broadly, DP thymocytes can adopt three different developmental fates based on the character of this interaction. The large majority of the thymocytes have no functional interaction between their TCRs and the MHC-self peptide complexes on the APCs, and die of neglect within a few days. Thymocytes expressing TCRs that have an interaction of intermediate strength undergo positive selection, after which they downregulate either the CD4 or CD8 coreceptor and exit the thymus as mature CD4 ϩ or CD8 ϩ T cells. Potentially autoreactive thymocytes, with TCRs that interact strongly with MHC-self peptide complexes, are deleted by an apoptotic process termed negative selection. How this continuum of different antigen receptor signal strengths leads to a discrete set of developmental outcomes, in terms of both lineage determination and survival, is still poorly understood.Numerous extracellular signals not involving the TCR have been implicated in the positive and...

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“…In particular, cytohesin-2 (ARNO) has been shown to participate in regulation of gene expression via the MAPK signaling pathway during serum-mediated transcriptional activation in nonimmune cells (68), whereas cytohesin-1 has been shown to be involved in activating the IL-2 gene promoter in T cells (51). Moreover, the scaffolding protein specifically interacting with cytohesin-1 in T cells, called cytohesin binder and regulator (Cybr), also has been shown to be involved in MAPKmediated and T cell antigen receptor-dependent gene transcription (12). These studies indicate that transcriptional regulation by cytohesins may be a widespread phenomenon among the small GEFs, and particular members of the cytohesin family could be regulated by cell type-specific interacting molecules.…”

Section: Discussionmentioning

confidence: 97%

Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution

Merkulova

Hurtado-Lorenzo

Hosokawa

et al. 2011

American Journal of Physiology-Cell Physiology

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Previously, we demonstrated that the vacuolar-type H(+)-ATPase (V-ATPase) a2-subunit functions as an endosomal pH sensor that interacts with the ADP-ribosylation factor (Arf) guanine nucleotide exchange factor, ARNO. In the present study, we showed that ARNO directly interacts not only with the a2-subunit but with all a-isoforms (a1-a4) of the V-ATPase, indicating a widespread regulatory interaction between V-ATPase and Arf GTPases. We then extended our search for other ARNO effectors that may modulate V-ATPase-dependent vesicular trafficking events and actin cytoskeleton remodeling. Pull-down experiments using cytosol of mouse proximal tubule cells (MTCs) showed that ARNO interacts with aldolase, but not with other enzymes of the glycolytic pathway. Direct interaction of aldolase with the pleckstrin homology domain of ARNO was revealed by pull-down assays using recombinant proteins, and surface plasmon resonance revealed their high avidity interaction with a dissociation constant: K(D) = 2.84 × 10(-10) M. MTC cell fractionation revealed that aldolase is also associated with membranes of early endosomes. Functionally, aldolase knockdown in HeLa cells produced striking morphological changes accompanied by long filamentous cell protrusions and acidic vesicle redistribution. However, the 50% knockdown we achieved did not modulate the acidification capacity of endosomal/lysosomal compartments. Finally, a combination of small interfering RNA knockdown and overexpression revealed that the expression of aldolase is inversely correlated with gelsolin levels in HeLa cells. In summary, we have shown that aldolase forms a complex with ARNO/Arf6 and the V-ATPase and that it may contribute to remodeling of the actin cytoskeleton and/or the trafficking and redistribution of V-ATPase-dependent acidic compartments via a combination of protein-protein interaction and gene expression mechanisms.

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Cytohesin Binder and Regulator Augments T Cell Receptor-induced Nuclear Factor of Activated T Cells·AP-1 Activation through Regulation of the JNK Pathway

Cited by 13 publications

References 45 publications

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer

Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer

Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes

Aldolase directly interacts with ARNO and modulates cell morphology and acidic vesicle distribution

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