The novel axis of YAP1, transcription enhancer factor 3 and Down Syndrome Candidate Region 1 isoform 1L is a common signaling pathway downstream of several angiogenic factors

AbstractVascular calcification (VC) is highly prevailing in cardiovascular disease, diabetes mellitus, and chronic kidney disease and, when present, is associated with cardiovascular events and mortality. The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is regarded as the foundation for mediating VC. Related transcriptional enhancer factor (RTEF-1), also named as transcriptional enhanced associate domain (TEAD) 4 or transcriptional enhancer factor-3 (TEF-3), is a nuclear transcriptional factor with a potent effect on cardiovascular diseases, apart from its oncogenic role in the canonical Hippo pathway. However, the role and mechanism of RTEF-1 in VC, particularly in calcification of VSMCs, are poorly understood. Our results showed that RTEF-1 was reduced in calcified VSMCs. RTEF-1 significantly ameliorated β-glycerophosphate (β-GP)-induced VSMCs calcification, as detected by alizarin red staining and calcium content assay. Also, RTEF-1 reduced alkaline phosphatase (ALP) activity and decreased expressions of osteoblast markers such as Osteocalcin and Runt-related transcription factor-2 (Runx2), but increased expression of contractile protein, including SM α-actin (α-SMA). Additionally, RTEF-1 inhibited β-GP-activated Wnt/β-catenin pathway which plays a critical role in calcification and osteogenic differentiation of VSMCs. Specifically, RTEF-1 reduced the levels of Wnt3a, p-β-catenin (Ser675), glycogen synthase kinase-3β (GSK-3β), and p-GSK-3β (Ser9), but increased the levels of p-β-catenin (Ser33/37). Also, RTEF-1 increased the ratio of p-β-catenin (Ser33/37) to β-catenin proteins and decreased the ratio of p-GSK-3β (Ser9) to GSK-3β protein. LiCl, a Wnt/β-catenin signaling activator, was observed to reverse the protective effect of RTEF-1 overexpression on VSMCs calcification induced by β-GP. Accordingly, Dickkopf-1 (Dkk1), a Wnt antagonist, attenuated the role of RTEF-1 deficiency in β-GP-induced VSMCs calcification. Taken together, we concluded that RTEF-1 ameliorated β-GP-induced calcification and osteoblastic differentiation of VSMCs by inhibiting Wnt/β-catenin signaling pathway.

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Transcription enhancer factor 1 interacts with a basic helix-loop-helix zipper protein, Max, for positive regulation of cardiac alpha-myosin heavy-chain gene expression.

Molecular and Cellular Biology ◽

10.1128/mcb.17.7.3924 ◽

1997 ◽

Vol 17 (7) ◽

pp. 3924-3936 ◽

Cited By ~ 61

Author(s):

M P Gupta ◽

C S Amin ◽

M Gupta ◽

N Hay ◽

R Zak

Keyword(s):

Myosin Heavy Chain ◽

Reporter Gene ◽

Heavy Chain ◽

Troponin T ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

E Box ◽

Two Factors ◽

Transcription Enhancer ◽

Enhancer Factor

The M-CAT binding factor transcription enhancer factor 1 (TEF-1) has been implicated in the regulation of several cardiac and skeletal muscle genes. Previously, we identified an E-box-M-CAT hybrid (EM) motif that is responsible for the basal and cyclic AMP-inducible expression of the rat cardiac alpha-myosin heavy chain (alpha-MHC) gene in cardiac myocytes. In this study, we report that two factors, TEF-1 and a basic helix-loop-helix leucine zipper protein, Max, bind to the alpha-MHC EM motif. We also found that Max was a part of the cardiac troponin T M-CAT-TEF-1 complex even when the DNA template did not contain an apparent E-box binding site. In the protein-protein interaction assay, a stable association of Max with TEF-1 was observed when glutathione S-transferase (GST)-TEF-1 or GST-Max was used to pull down in vitro-translated Max or TEF-1, respectively. In addition, Max was coimmunoprecipitated with TEF-1, thus documenting an in vivo TEF-1-Max interaction. In the transient transcription assay, overexpression of either Max or TEF-1 resulted a mild activation of the alpha-MHC-chloramphenicol acetyltransferase (CAT) reporter gene at lower concentrations and repression of this gene at higher concentrations. However, when Max and TEF-1 expression plasmids were transfected together, the repression mediated by a single expression plasmid was alleviated and a three- to fourfold transactivation of the alpha-MHC-CAT reporter gene was observed. This effect was abolished once the EM motif in the promoter-reporter construct was mutated, thus suggesting that the synergistic transactivation function of the TEF-1-Max heterotypic complex is mediated through binding of the complex to the EM motif. These results demonstrate a novel association between Max and TEF-1 and indicate a positive cooperation between these two factors in alpha-MHC gene regulation.

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Down Syndrome Candidate Region 1 (DSCR1)

Encyclopedia of Signaling Molecules ◽

10.1007/978-1-4419-0461-4_100361 ◽

2012 ◽

pp. 530-530

Author(s):

Thomas J. Lukas ◽

Daniela V. Rosa ◽

Luiz Alexandre V. Magno ◽

Bruno R. Souza ◽

Marco A. Romano-Silva ◽

...

Keyword(s):

Down Syndrome ◽

Candidate Region

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Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.772734 ◽

2021 ◽

Vol 15 ◽

Author(s):

Cesar Sierra ◽

Ilario De Toma ◽

Lorenzo Lo Cascio ◽

Esteban Vegas ◽

Mara Dierssen

Keyword(s):

Down Syndrome ◽

Object Recognition ◽

Environmental Factors ◽

Mouse Models ◽

Recognition Task ◽

Novel Object Recognition ◽

The Novel ◽

Wild Type ◽

Male And Female ◽

Novel Object

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.

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Cbsoverdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically withDyrk1a

10.1101/393579 ◽

2018 ◽

Cited By ~ 1

Author(s):

Damien Marechal ◽

Véronique Brault ◽

Alice Leon ◽

Dehren Martin ◽

Patricia Lopes Pereira ◽

...

Keyword(s):

Down Syndrome ◽

Object Recognition ◽

Synaptic Transmission ◽

Actin Cytoskeleton ◽

Epistatic Interaction ◽

Novel Object Recognition ◽

The Novel ◽

Novel Object ◽

Cystathionine Beta Synthase ◽

Necessary And Sufficient

ABSTRACTIdentifying dosage sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) show cognitive phenotype and needs to be investigated to identify the main genetic driver. Here, we report that, in the Dp1Yah mice, 3 copies of the Cystathionine-beta-synthase gene (Cbs)are necessary to observe a deficit in the novel object recognition (NOR) paradigm. Moreover, the overexpression ofCbsalone is sufficient to induce NOR deficit. Accordingly targeting the overexpression of human CBS, specifically in Camk2a-expressing neurons, leads to impaired objects discrimination. Altogether this shows thatCbsoverdosage is involved in DS learning and memory phenotypes. In order to go further, we identified compounds that interfere with the phenotypical consequence of CBS overdosage in yeast. Pharmacological intervention in the Tg(CBS) with one selected compound restored memory in the novel object recognition. In addition, using a genetic approach, we demonstrated an epistatic interaction betweenCbsandDyrk1a, another human chromosome 21 gene encoding the dual-specificity tyrosine phosphorylation-regulated kinase 1a and an already known target for DS therapeutic intervention. Further analysis using proteomic approaches highlighted several pathways, including synaptic transmission, cell projection morphogenesis, and actin cytoskeleton, that are affected by DYRK1A and CBS overexpression. Overall we demonstrated that CBS overdosage underpins the DS-related recognition memory deficit and that bothCBSandDYRK1Ainteract to control accurate memory processes in DS. In addition, our study establishes CBS as an intervention point for treating intellectual deficiencies linked to DS.SIGNIFICANT STATEMENTHere, we investigated a region homologous to Hsa21 and located on mouse chromosome 17. We demonstrated using three independent genetic approaches that the overdosage of the Cystathionine-beta-synthase gene (Cbs) gene, encoded in the segment, is necessary and sufficient to induce deficit in novel object recognition (NR).In addition, we identified compounds that interfere with the phenotypical consequence of CBS overdosage in yeast and in mouse transgenic lines. Then we analyzed the relation between Cbs overdosage and the consequence of DYRK1a overexpression, a main driver of another region homologous to Hsa21 and we demonstrated that an epistatic interaction exist betweenCbsandDyrk1aaffecting different pathways, including synaptic transmission, cell projection morphogenesis, and actin cytoskeleton.

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