Publication Date:
2011-04-19
Description:
Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598045/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598045/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guarani, Virginia -- Deflorian, Gianluca -- Franco, Claudio A -- Kruger, Marcus -- Phng, Li-Kun -- Bentley, Katie -- Toussaint, Louise -- Dequiedt, Franck -- Mostoslavsky, Raul -- Schmidt, Mirko H H -- Zimmermann, Barbara -- Brandes, Ralf P -- Mione, Marina -- Westphal, Christoph H -- Braun, Thomas -- Zeiher, Andreas M -- Gerhardt, Holger -- Dimmeler, Stefanie -- Potente, Michael -- R01 DK088190/DK/NIDDK NIH HHS/ -- R01 GM093072/GM/NIGMS NIH HHS/ -- R01DK088190-01A1/DK/NIDDK NIH HHS/ -- R01GM093072-01/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 May 12;473(7346):234-8. doi: 10.1038/nature09917. Epub 2011 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, D-60590 Frankfurt, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21499261" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylation
;
Animals
;
Endothelial Cells/cytology/*enzymology
;
*Gene Expression Regulation
;
Gene Knockout Techniques
;
Gene Silencing
;
HEK293 Cells
;
Humans
;
Mice
;
Mutation
;
Receptor, Notch1/metabolism
;
Receptors, Notch/*metabolism
;
Signal Transduction/*physiology
;
Sirtuin 1/*genetics/*metabolism
;
Zebrafish/embryology/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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