Amino-terminal Enhancer of Split (AES) Interacts with the Oncoprotein NUP98-HOXA9 and Enhances Its Transforming Ability

Sarma, Nayan J.; Yaseen, Nabeel R.

doi:10.1074/jbc.m111.297952

Cited by 9 publications

(14 citation statements)

References 69 publications

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“…Together with our observation of an interaction between GRG5/AES and TCF4 this prompted us to examine the ability of GRG5/AES to counteract TCF-β-catenin-mediated transcription (Figure 6). As previously observed in other cell lines [71], co-transfection of HEK293 cell line with a TCF-Luc construct (containing three TCF consensus binding sites upstream of the firefly luciferase cDNA) together with β-catenin resulted in a remarkable increase of luciferase activity compared to TCF-Luc expression alone (Figure 6A). Addition of increasing amounts of GRG5/AES plasmid reduced luciferase reporter activation in a dose-dependent manner (Figure 6A).…”

Section: Resultssupporting

confidence: 82%

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GRG5/AES Interacts with T-Cell Factor 4 (TCF4) and Downregulates Wnt Signaling in Human Cells and Zebrafish Embryos

et al. 2013

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Transcriptional control by TCF/LEF proteins is crucial in key developmental processes such as embryo polarity, tissue architecture and cell fate determination. TCFs associate with β-catenin to activate transcription in the presence of Wnt signaling, but in its absence act as repressors together with Groucho-family proteins (GRGs). TCF4 is critical in vertebrate intestinal epithelium, where TCF4-β-catenin complexes are necessary for the maintenance of a proliferative compartment, and their abnormal formation initiates tumorigenesis. However, the extent of TCF4-GRG complexes’ roles in development and the mechanisms by which they repress transcription are not completely understood. Here we characterize the interaction between TCF4 and GRG5/AES, a Groucho family member whose functional relationship with TCFs has been controversial. We map the core GRG interaction region in TCF4 to a 111-amino acid fragment and show that, in contrast to other GRGs, GRG5/AES-binding specifically depends on a 4-amino acid motif (LVPQ) present only in TCF3 and some TCF4 isoforms. We further demonstrate that GRG5/AES represses Wnt-mediated transcription both in human cells and zebrafish embryos. Importantly, we provide the first evidence of an inherent repressive function of GRG5/AES in dorsal-ventral patterning during early zebrafish embryogenesis. These results improve our understanding of TCF-GRG interactions, have significant implications for models of transcriptional repression by TCF-GRG complexes, and lay the groundwork for in depth direct assessment of the potential role of Groucho-family proteins in both normal and abnormal development.

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Section: Resultssupporting

confidence: 82%

“…TCF-Luc (containing three TCF consensus binding sites - TREs) and TCF*-Luc (with three mutant TCF binding sites) were previously described [71]. For pB15UT-Luc, 3 copies of the 5 Gal4 upstream activation sequences (UAS G ) present in UAS G -βgal [70] were concatamerized and used to replace the TREs in TCF-Luc.…”

Section: Methodsmentioning

confidence: 99%

GRG5/AES Interacts with T-Cell Factor 4 (TCF4) and Downregulates Wnt Signaling in Human Cells and Zebrafish Embryos

et al. 2013

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“…Immunostaining was done as described before [22]. Briefly, cells were fixed with 4% paraformaldehyde and permeabilized with 0.1% Triton X-100.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoprecipitation of P65 with CEBPα or the reverse immunoprecipiation in TNFα treated hepatocytes (1×10 6 ) were carried out as described by Sarma et al [22]. Briefly, cells were washed with DPBS, and lysed with 0.5 ml of lysis buffer (10 mM Tris-HCl, pH 7.5, 0.4 M NaCl, 1% Nonidet P-40, 0.4% Triton X-100, 0.2% sodium deoxycholate, 1 mM EDTA, protease inhibitors (PI), 1 mM PMSF).…”

Section: Methodsmentioning

confidence: 99%

Hepatitis C Virus Mediated Changes in miRNA-449a Modulates Inflammatory Biomarker YKL40 through Components of the NOTCH Signaling Pathway

et al. 2012

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Liver disease due to hepatitis C virus (HCV) infection is an important health problem worldwide. HCV induced changes in microRNAs (miRNA) are shown to mediate inflammation leading to liver fibrosis. Gene expression analyses identified dysregulation of miRNA-449a in HCV patients but not in alcoholic and non-alcoholic liver diseases. By sequence analysis of the promoter for YKL40, an inflammatory marker upregulated in patients with chronic liver diseases with fibrosis, adjacent binding sites for nuclear factor of Kappa B/P65 and CCAAT/enhancer-binding protein alpha (CEBPα) were identified. P65 interacted with CEBPα to co-operatively activate YKL40 expression through sequence specific DNA binding. In vitro analysis demonstrated that tumor necrosis factor alpha (TNFα) mediated YKL40 expression is regulated by miRNA-449a and its target NOTCH1 in human hepatocytes.NOTCH1 facilitated nuclear localization of P65 in response to TNFα. Further, HCV patients demonstrated upregulation of NOTCH1 along with downregulation of miRNA-449a. Taken together it is demonstrated that miRNA-449a plays an important role in modulating expression of YKL40 through targeting the components of the NOTCH signaling pathway following HCV infection. Therefore, defining transcriptional regulatory mechanisms which control inflammatory responses and fibrosis will be important towards developing strategies to prevent hepatic fibrosis especially following HCV recurrence in liver transplant recipients.

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“…Importantly, AES interacts with both wild type NUP98 and NUP98-HOXA9, consistent with the idea of a conserved, nucleoporin-dependent mechanism of transcriptional regulation that is hijacked in leukemogenesis. Together, AES and NUP98-HOXA9 cooperate to regulate transcription, cell transformation and the impairment of hematopoietic differentiation 79 , 80 …”

Section: Relevance To Leukemia: Nucleoporins As Transcription Factorsmentioning

confidence: 99%

The new nucleoporin

Sarma

Willis

2012

Nucleus

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Transcriptional regulation is a complex process that requires the integrated action of many multi-protein complexes. The way in which a living cell coordinates the action of these complexes in time and space is still poorly understood. Recent work has shown that nuclear pores, well known for their role in 3′ processing and export of transcripts, also participate in the control of transcriptional initiation. We have recently begun to explore how nuclear pores interface with the well-described machinery that regulates initiation. This work led to the discovery that specific nucleoporins are required for binding of the repressor protein Mig1 to its site in target promoters. Nuclear pores are therefore involved in repressing, as well as activating, transcription. Here we discuss in detail the main models explaining our result and consider what each implies about the roles that nuclear pores play in the regulation of gene expression.

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Amino-terminal Enhancer of Split (AES) Interacts with the Oncoprotein NUP98-HOXA9 and Enhances Its Transforming Ability

Cited by 9 publications

References 69 publications

GRG5/AES Interacts with T-Cell Factor 4 (TCF4) and Downregulates Wnt Signaling in Human Cells and Zebrafish Embryos

GRG5/AES Interacts with T-Cell Factor 4 (TCF4) and Downregulates Wnt Signaling in Human Cells and Zebrafish Embryos

Hepatitis C Virus Mediated Changes in miRNA-449a Modulates Inflammatory Biomarker YKL40 through Components of the NOTCH Signaling Pathway

The new nucleoporin

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