ErbB3 binding protein 1 (EBP1) participates in the regulation of intestinal inflammation via mediating Akt signaling pathway

Miao, Xianjing; Tang, Qiyun; Miao, Xiaobing; Wu, Yong; Qian, Ji; Zhao, Weijuan; Wang, Liang; Li, Liren; Zhang, Dongmei

doi:10.1016/j.molimm.2015.07.032

Cited by 12 publications

(12 citation statements)

References 39 publications

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“…PA2G4 was originally identified as a cell-cycle-regulated protein (human homolog of the mouse protein p38-2AG4) and then an ErbB3-binding protein (43,44). Subsequent studies showed that PA2G4 belongs to a family of DNA/RNA binding proteins implicated in cell growth, apoptosis, and differentiation (45). The longer PA2G4 isoform, p48 (375 amino acids), was ubiquitously expressed in the cytoplasm and nucleus, and suppressed apoptosis (15).…”

Section: Discussionmentioning

confidence: 99%

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

et al. 2019

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MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferationassociated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCNdependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease.Significance: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCNbinding partners in malignancies driven by MYC family oncoproteins. Characterization of the PA2G4-MYCN protein-protein interface. A, GST pulldown of overexpressed GST-MYCN deletion mutant proteins and a PA2G4-3xFlag expression vector for 24 hours in HEK-293T cells, which were then immunoblotted with an anti-Flag antibody. B, Overlay of the independent representation of the docking solutions of WS6 (green carbons) and the MYCN oligopeptide DHKALST (white carbons) to PA2G4. Both were predicted to bind to the same surface pocket of PA2G4 (gray-filled space). C, A representative SPR (Biacore T200) experiment demonstrating a direct dose-response binding interaction between the bound PA2G4 exposed to increasing concentrations of the MYCN oligopeptide, DHKALST. Each experiment was run in duplicate. Overall this interaction had a calculated K d of 28.3 AE 0.73 mmol/L (n ¼ 5). D, A molecular model of the PA2G4-MYCN protein interface. The addition of two MYCN amino acids at the C-terminus and five at the N-terminus of the DHKALST MYCN oligopeptide resulted in an oligopeptide, GGDHKALSTGEDTL (cyan carbons), which interacted with PA2G4 (white carbons) in this molecular model. A visual analysis of this static dock predicted putative hydrogen bonds (yellow dashes) with residues Ser47, Arg271, and Arg272, which were subsequently targeted for mutagenesis. E, Representative SPR curves showing the concentration-response binding of DHKALST to PA2G4 (solid lines). The addition of 10 mmol/L WS6 resulted in a repression of this binding (dotted lines). This experiment was conducted in duplicate, three times. F, HEK293 cells were transiently transfecte...

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Section: Discussionmentioning

confidence: 99%

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

et al. 2019

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Section: Discussionmentioning

confidence: 99%

“…The biological effects of EBP1 vary depending on cell type and context, although the precise mechanisms for the differential roles and regulation of EBP1 in different tissues have not been defined (Miao et al 2015;Pisapia et al 2015;Hwang et al 2016). Previous study showed that Ebp1 is weakly expressed in mouse skeletal muscles, and its expression is higher in activated versus quiescent satellite cells (Squatrito et al 2004;Pallafacchina et al 2010;Figeac et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Ebp1 was strongly induced during myoblast activation, remaining at high levels during proliferation and differentiation. Previous studies have shown that EBP1 plays a crucial role in the growth of many cancer cells by interacting with other proteins (Zhou et al 2011;Miao et al 2015;Zhang et al 2015). However, the molecular mechanisms of Ebp1 on the development of myoblasts are unclear.…”

Section: Introductionmentioning

confidence: 99%

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Ebp1 regulates myogenic differentiation of myoblast cells via SMAD2/3 signaling pathway

Wang

Liu

et al. 2017

Dev Growth Differ

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Regulation of skeletal muscle development requires many of the regulatory networks that are fundamental to developmental myogenesis. ErbB3 binding protein-1 (Ebp1) is involved in the control of myoblasts development in chicken. However, the expression and biological functions of Ebp1 in the progress of myogenesis are unclear. This study focused on determining the effect of Ebp1 on myogenic proliferation and differentiation using a primary myoblasts culture model. Ebp1 was found to upregulate in proliferating myoblasts and decrease at the early stage of myogenic differentiation. The level of endogenous Ebp1 increased from E9 to E20 chicken leg muscles. Knockdown of Ebp1 had no effect on myoblasts proliferation. However, myogenic differentiation into multinucleated myotubes was significantly reduced. The mRNA and protein expression of MRFs was decreased when Ebp1 was knocked down. Downregulation of Ebp1, accompanied by elevated levels of pSMAD2/3, suggests that Ebp1 is involved in regulating myogenic differentiation via SMAD2/3 inhibition. The phosphorylation of SMAD2/3 was activated and the expression of MYOD and MYOG was reduced in Ebp1 knockdown myoblasts, but addition of LY2109761 (an inhibitor specified to SMAD2/3) blocked these effects. Collectively, these results indicate that Ebp1 promotes myoblast differentiation by inhibition of SMAD2/3 signaling pathway during chicken myogenesis. These data provide new insights into the biological role of Ebp1 in embryonic chicken skeletal muscle development.

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“…Additionally, PA2G4 associated with cell growth, differentiation, and apoptosis was upregulated in both Mz4 and Gc in the present study. A recent study indicated that PA2G4 negatively regulated intestinal inflammation by mediating the Akt signaling pathway [ 64 ]. Similarly, the upregulation of PA2G4 in both Mz4 and Gc of E. stiedae , to some extent, suggested that it might be capable of escaping immune responses by attenuating inflammatory damage of its host, as previously described [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Global transcriptome landscape of the rabbit protozoan parasite Eimeria stiedae

et al. 2021

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Background Coccidiosis caused by Eimeria stiedae is a widespread and economically significant disease of rabbits. The lack of studies on the life-cycle development and host interactions of E. stiedae at the molecular level has hampered our understanding of its pathogenesis. Methods In this study, we present a comprehensive transcriptome landscape of E. stiedae to illustrate its dynamic development from unsporulated oocysts to sporulated oocysts, merozoites, and gametocytes, and to identify genes related to parasite-host interactions during parasitism using combined PacBio single-molecule real-time and Illumina RNA sequencing followed by bioinformatics analysis and qRT-PCR validation. Results In total, 12,582 non-redundant full-length transcripts were generated with an average length of 1808 bp from the life-cycle stages of E. stiedae. Pairwise comparisons between stages revealed 8775 differentially expressed genes (DEGs) showing highly significant description changes, which compiled a snapshot of the mechanisms underlining asexual and sexual biology of E. stiedae including oocyst sporulation between unsporulated and sporulated oocysts; merozoite replication between sporulated oocysts and merozoites; and gametophyte development and gamete generation between merozoites and gametocytes. Further, 248 DEGs were grouped into nine series clusters and five groups by expression patterns, and showed that parasite–host interaction-related genes predominated in merozoites and gametocytes and were mostly involved in steroid biosynthesis and lipid metabolism and carboxylic acid. Additionally, co-expression analyses identified genes associated with development and host invasion in unsporulated and sporulated oocysts and immune interactions during gametocyte parasitism. Conclusions This is the first study, to our knowledge, to use the global transcriptome profiles to decipher molecular changes across the E. stiedae life cycle, and these results not only provide important information for the molecular characterization of E. stiedae, but also offer valuable resources to study other apicomplexan parasites with veterinary and public significance. Graphic Abstract

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ErbB3 binding protein 1 (EBP1) participates in the regulation of intestinal inflammation via mediating Akt signaling pathway

Cited by 12 publications

References 39 publications

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface

Ebp1 regulates myogenic differentiation of myoblast cells via SMAD2/3 signaling pathway

Global transcriptome landscape of the rabbit protozoan parasite Eimeria stiedae

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