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Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase (2011)

V. Guarani ; G. Deflorian ; C. A. Franco ; [et al.]

Nature Publishing Group (NPG)

In: Nature. 473(7346): 234-8. doi: 10.1038/nature09917.

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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

Published by Nature Publishing Group (NPG)

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Transport and magnetic properties of polycrystalline Nd1.85Ce0.15CuO4−y under applied magnetic fields : 37th Annual conference on magnetism and magnetic materials (1993)

Barbeta, V. B. ; Westphal, C. H. ; Jardim, R. F. ; [et al.]

[S.l.] : American Institute of Physics (AIP)

Journal of Applied Physics 73 (1993), S. 6639-6641

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ISSN: 1089-7550

Source: AIP Digital Archive

Topics: Physics

Notes: Systematic studies of transport and magnetic properties on polycrystalline Nd1.85Ce0.15CuO4−y specimens under applied magnetic fields as high as 8 kOe have revealed strong evidence of granularity in this system. Electrical resistivity measurements show two superconducting transitions. One of the transitions occurs at higher temperature and is almost insensitive to applied magnetic field and current density, while the other one occurs at lower temperature and is strongly modified by the application of magnetic field and changes in the current density. In the low-field limit (H〈100 Oe), a drastic broadening of the superconducting transition is observed. Magnetic susceptibility χac measurements show similar features. There are two well-defined contributions to the diamagnetic signal below 20 K which are particularly evident in the resistive component of χac where two peaks can be identified. The application of an applied magnetic field shifts both peaks towards low temperatures. All the results can be satisfactorily explained in terms of weakly linked Josephson junctions between superconducting islands. The islands have a superconducting transition at higher temperature, and the long-range order phase coherence is achieved through Josephson coupling at lower temperatures.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.352539

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Properties of polycrystalline (Nd1−xGdx)1.85Ce0.15CuO4−y compounds : The 41st annual conference on magnetism and magnetic materials (1997)

Jardim, R. F. ; Westphal, C. H. ; Becerra, C. C. ; [et al.]

[S.l.] : American Institute of Physics (AIP)

Journal of Applied Physics 81 (1997), S. 4250-4252

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ISSN: 1089-7550

Source: AIP Digital Archive

Topics: Physics

Notes: We have studied the structural, magnetic, and transport properties of polycrystalline (Nd1−xGdx)1.85Ce0.15CuO4−y; x=0.0, 0.05, 0.10, 0.25, and 0.50; produced under different atmospheres and cooling rates after the reduction process. From x-ray analysis the T′-structure is preserved for all samples studied. We also found that quenched samples in argon atmosphere exhibit superconductivity below ∼22 K. The temperature dependence of the electrical resistivity ρ(T) displays a striking double resistive superconducting transition with no evidence of a zero resistance state down to 1.5 K. The electrical resistivity has a (approximate)20% drop at the upper critical temperature Tci followed by a plateau down to a lower temperature Tcj. While Tci is both weakly dependent on the Gd content and external applied magnetic field, the behavior of ρ(T) at low temperatures is strongly sensitive to the Gd concentration, excitation current, and applied magnetic fields. Also, the behavior of ρ(T) below (approximate)3 K is almost field independent. The magnetic susceptibility data χ(T) reveal superconductivity below Tci and a reentrantlike behavior at low temperatures where the magnitude of χ(T) increases rapidly with decreasing temperature. These observations are similar to those observed in granular Ga films close to the nonmetallic side of the superconductor-insulator transition. We argue that these compounds can be understood within the framework of a superconducting granular model. © 1997 American Institute of Physics.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.365137

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Magnetic properties of polycrystalline Sm2−xCexCuO4−y at high magnetic fields : The 40th annual conference on magnetism and magnetic materials (1996)

Jardim, R. F. ; Westphal, C. H. ; Cohenca, C. H. ; [et al.]

[S.l.] : American Institute of Physics (AIP)

Journal of Applied Physics 79 (1996), S. 6564-6566

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ISSN: 1089-7550

Source: AIP Digital Archive

Topics: Physics

Notes: We have performed measurements of ac magnetic susceptibility χac as a function of temperature and magnetic field on polycrystalline specimens of Sm2−xCexCuO4−y (0.15≤x≤0.18) prepared from a sol-gel precursor. All the samples studied show a striking double resistive superconducting transition. One of the resistive transitions occurs at a higher temperature Tci and the other one at a lower Josephson-coupling temperature Tcj. Magnetic measurements reveal the appearance of superconductivity below Tcj which is evident from the resistive component χ″ which peaks only at Tcj. Measurements made on pellets and crushed samples with average grain size ∼1 μm show essentially the same features. This suggests that Josephson coupling occurs inside physical grains with dimensions close to 5 μm. We have also utilized the behavior of the peak in the χ″ component as a function of applied magnetic fields to build a H vs T phase diagram for these compounds. Some interesting features were observed in this H vs T phase diagram: (1) a Hα, α=2/3, dependence at low applied magnetic fields (H≤2 kOe) and high temperatures, and (2) an abrupt increase in the magnitude of the exponent at high fields and low temperatures. The behavior at low fields and high temperatures suggests that the magnetic response of the system is mainly controlled by a disordered Josephson network. Possible connections between these two different behaviors are discussed. © 1996 American Institute of Physics.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.361947

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Transport and magnetic properties of polycrystalline Sm2−xCexCuO4−y : 38th Annual Conference on Magnetism and Magnetic Materials (1994)

Jardim, R. F. ; Westphal, C. H. ; Cohenca, C. H. ; [et al.]

[S.l.] : American Institute of Physics (AIP)

Journal of Applied Physics 75 (1994), S. 6720-6722

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ISSN: 1089-7550

Source: AIP Digital Archive

Topics: Physics

Notes: A systematic study of transport and magnetic properties of polycrystalline Sm2−xCexCuO4−y (0.15≤x(very-much-less-than)0.18) specimens obtained from a sol-gel precursor reveals a striking double resistive superconducting transition. One of the resistive transitions takes place at a temperature Tci and is almost insensitive to Ce concentration, applied magnetic field, and current density, while the other transition occurs at a lower temperature Tcj and is very sensitive to Ce content, applied magnetic field, and current density. Alternating-current magnetic susceptibility χac measurements reveal two interesting features. There is only one contribution to the diamagnetic signal below ∼20 K, which is particularly evident in the resistive component χ‘ of χac where a peak at Tcj can be identified. The application of an applied magnetic field shifts the χ‘ peak to lower temperatures and reveals a spin-glass-like behavior. All the results can be satisfactorily explained in terms of weakly linked Josephson junctions between small superconducting islands. The small islands have a superconducting transition at a higher temperature Tci, and the long-range phase coherence is achieved through Josephson coupling at lower temperatures Tcj. All the results suggest a superconducting glass state in a disordered Josephson network.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.356849

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Magnetic properties of polycrystalline LnNi0.3Co0.7O3 (Ln=La, Pr) compounds (2000)

Escote, M. T. ; Westphal, C. H. ; Jardim, R. F.

[S.l.] : American Institute of Physics (AIP)

Journal of Applied Physics 87 (2000), S. 5908-5910

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ISSN: 1089-7550

Source: AIP Digital Archive

Topics: Physics

Notes: Polycrystalline samples of LnNi0.3Co0.7O3 (Ln=La, Pr) were prepared through sol-gel precursors. The samples were subjected to several heat treatments at temperatures ranging from 650 to 1000 °C and under oxygen pressure as high as 70 bar. Characterizations of x-ray powder diffraction XRD magnetization M(T), and ac magnetic susceptibility χac(T) were performed on these compounds. The results of XRD showed that samples of LaNi0.3Co0.7O3 crystallize in a rhombohedral distorted perovskite structure (R3¯c) and that PrNi0.3Co0.7O3 compounds displayed an orthorhombically distorted structure (Pbnm). The temperature dependence of M(T) revealed the presence of a sharp cusp occurring at temperatures TP∼60 and ∼ 30 K for Ln=La and Pr, respectively. Below TP, the M(T) curves taken after different thermal cycles, i.e., field cooled and zero-field cooled processes, are histories dependent on the magnitude of M(T) decreasing with increasing applied magnetic field. We have also observed that TP decreases with increasing applied magnetic field. Measurements of χac(T) at zero applied magnetic field in all samples studied revealed one peak anomaly occurring at temperatures Tf=58 and 30 K for La and Pr, respectively. In fact, increasing frequency over four orders of magnitude results in a shift of the peak anomaly to higher temperatures, as expected for a spin-glass system. Also, a broadening of the peak anomaly is observed with the application of an external magnetic field and it evolves in two peaks at H as high as ∼ 500 Oe. Thus the χac(T) curves reveal two well-defined peaks: one, which is essentially frequency independent and another that is shifted to higher temperatures with increasing frequency. The origin of these magnetic behaviors is discussed. © 2000 American Institute of Physics.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1063/1.372563

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