Evidence map›Paper›PMID 24847033›Full record

ArticleJournal of the American Heart Association2014

Phosphorylation of Shox2 is required for its function to control sinoatrial node formation.

Hongbing Liu, Chao-Hui Chen, Wenduo Ye, Ramón A Espinoza-Lewis, Xuefeng Hu, Yanding Zhang, YiPing Chen

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of the American Heart Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
0.7field-weighted citation impact, top 29% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

10 citing papers in PubMed, 18 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 2 countries.

Hongbing LiuDepartment of Cell and Molecular Biology, Tulane University, New Orleans, 70118, LA (H.L., C.H.C., W.Y., R.E.L., Y.P.C.).
Chao-Hui ChenDepartment of Cell and Molecular Biology, Tulane University, New Orleans, 70118, LA (H.L., C.H.C., W.Y., R.E.L., Y.P.C.).
Wenduo YeDepartment of Cell and Molecular Biology, Tulane University, New Orleans, 70118, LA (H.L., C.H.C., W.Y., R.E.L., Y.P.C.).
Ramón A Espinoza-LewisDepartment of Cell and Molecular Biology, Tulane University, New Orleans, 70118, LA (H.L., C.H.C., W.Y., R.E.L., Y.P.C.) Division of Cardiology, Children's Hospital Boston and Harvard Medical School, Boston, MA.
Xuefeng HuCenter for Biomedical Research of South China, Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province, China (X.H., Y.Z., Y.P.C.).
Yanding ZhangCenter for Biomedical Research of South China, Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province, China (X.H., Y.Z., Y.P.C.).
YiPing ChenDepartment of Cell and Molecular Biology, Tulane University, New Orleans, 70118, LA (H.L., C.H.C., W.Y., R.E.L., Y.P.C.) Center for Biomedical Research of South China, Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Science, Fujian Normal University, Fuzhou, Fujian Province, China (X.H., Y.Z., Y.P.C.).
Tulane University · USFujian Normal University · CN

Funding

Shox2 and temporomandibular joint formationR01DE017792 · NIDCR · TULANE UNIVERSITY OF LOUISIANA · PI CHEN, YIPING · 2009 to 2013
$1.7M
NIDCR NIH HHS R01 DE017792
6 · The paper itself

Abstract

backgroundInactivation of Shox2, a member of the short-stature homeobox gene family, leads to defective development of multiple organs and embryonic lethality as a result of cardiovascular defects, including bradycardia and severe hypoplastic sinoatrial node (SAN) and sinus valves, in mice. It has been demonstrated that Shox2 regulates a genetic network through the repression of Nkx2.5 to maintain the fate of the SAN cells. However, the functional mechanism of Shox2 protein as a transcriptional repressor on Nkx2.5 expression remains completely unknown. METHODS AND

resultsA specific interaction between the B56δ regulatory subunit of PP2A and Shox2a, the isoform that is expressed in the developing heart, was demonstrated by yeast 2-hybrid screen and coimmunoprecipitation. Western blotting and immunohistochemical assays further confirmed the presence of phosphorylated Shox2a (p-Shox2a) in cell culture as well as in the developing mouse and human SAN. Site-directed mutagenesis and in vitro kinase assays identified Ser92 and Ser110 as true phosphorylation sites and substrates of extracellular signal-regulated kinase 1 and 2. Despite that Shox2a and its phosphorylation mutants possessed similar transcriptional repressive activities in cell cultures when fused with Gal4 protein, the mutant forms exhibited a compromised repressive effect on the activity of the mouse Nkx2.5 promoter in cell cultures, indicating that phosphorylation is required for Shox2a to repress Nkx2.5 expression specifically. Transgenic expression of Shox2a, but not Shox2a-S92AS110A, mutant in the developing heart resulted in down-regulation of Nkx2.5 in wild-type mice and rescued the SAN defects in the Shox2 mutant background. Last, we demonstrated that elimination of both phosphorylation sites on Shox2a did not alter its nuclear location and dimerization, but depleted its capability to bind to the consensus sequences within the Nkx2.5 promoter region.

conclusionsOur studies reveal that phosphorylation is essential for Shox2a to repress Nkx2.5 expression during SAN development and differentiation.

Indexed as

AnimalsCells, CulturedElectrophoretic Mobility Shift AssayGene Expression Regulation, DevelopmentalHeart RateHomeobox Protein Nkx-2.5Homeodomain ProteinsHumansMiceMice, TransgenicMutagenesis, Site-DirectedPhosphorylationReal-Time Polymerase Chain ReactionSinoatrial NodeTranscription FactorsTwo-Hybrid System TechniquesHomeobox Protein Nkx-2.5Homeodomain ProteinsNKX2-5 protein, humanNkx2-5 protein, mouseSHOX2 protein, humanShox2 protein, mouseTranscription FactorsDNA bindingNkx2.5 repressionpacemakingphosphorylationSAN developmentShox2

Identifiers

PMID24847033
PMCPMC4309068
OpenAlexW2121202965

What OpenQuestion holds

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LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.