β-Catenin C-terminal signals suppress p53 and are essential for artery formation.

Dario F Riascos-Bernal,Longyue Cao,Charlene M Dunaway,Konrad Basler,Prameladevi Chinnasamy,Nicholas E S Sibinga,Tomas Valenta

doi:10.1038/ncomms12389

Dario F Riascos-Bernal, Longyue Cao + Show 5 more

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https://doi.org/10.1038/ncomms12389

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Abstract

Increased activity of the tumour suppressor p53 is incompatible with embryogenesis, but how p53 is controlled is not fully understood. Differential requirements for p53 inhibitors Mdm2 and Mdm4 during development suggest that these control mechanisms are context-dependent. Artery formation requires investment of nascent endothelial tubes by smooth muscle cells (SMCs). Here, we find that embryos lacking SMC β-catenin suffer impaired arterial maturation and die by E12.5, with increased vascular wall p53 activity. β-Catenin-deficient SMCs show no change in p53 levels, but greater p53 acetylation and activity, plus impaired growth and survival. In vivo, SMC p53 inactivation suppresses phenotypes caused by loss of β-catenin. Mechanistically, β-catenin C-terminal interactions inhibit Creb-binding protein-dependent p53 acetylation and p53 transcriptional activity, and are required for artery formation. Thus in SMCs, the β-catenin C-terminus indirectly represses p53, and this function is essential for embryogenesis. These findings have implications for angiogenesis, tissue engineering and vascular disease.

Highlights

Increased activity of the tumour suppressor p53 is incompatible with embryogenesis, but how p53 is controlled is not fully understood
smooth muscle cells (SMCs) b-catenin is essential for artery formation
Possibly due to different transgene integration site or modest variation in level, timing or distribution of Tagln-Cre expression or strain background, we observe that b-catenin loss in SMCs impairs artery formation, as reflected by thinned and dilated major vessels observed before any evident cardiac abnormality

Summary

Introduction

Increased activity of the tumour suppressor p53 is incompatible with embryogenesis, but how p53 is controlled is not fully understood. Mdm[2] and Mdm[4] are the major p53 inhibitors[4], the differential requirement for Mdm[2] and Mdm[4] in cardiac and central nervous system development[5] raises the possibility that cell type-specific mechanisms restrain p53 during embryogenesis This is especially intriguing during artery formation: smooth muscle cells (SMCs) constitute the main component of the arterial wall, requirements for Mdm[2] or Mdm[4] have not been evaluated in this cell type, and how SMCs repress p53 function to proliferate, survive and build the arterial wall is unknown. B-catenin performs this function in part by inhibiting p53 activity

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