The gaseous messenger nitric oxide (NO) contributes to biological effects of oestrogen in target tissues, including reproductive organs, bone, cardiovascular and central nervous systems. Vasodilation and anti-atherosclerotic properties of NO have been shown to play a role in these effects. The possibility that NO acts also through regulation of the signal transduction cascade triggered by oestrogen, instead, has never been investigated. To study this we have used the MCF-7 human breast cancer cell line, an established model for oestrogen signalling. Exposure of these cells to 17-β-oestradiol (E2) in the presence of NO gave rise to activation of signalling events additional to those triggered by E2 alone, namely tyrosine phosphorylation of specific proteins, including the insulin receptor substrate-1, with recruitment to this adapter of the phosphatidylinositol 3′-kinase and persistent activation of Akt (protein kinase B). Active Akt, in turn, prevented E2 from activating p42/44 extracellular signal-regulated kinases (ERK 1/2). These effects of NO, which were mediated through generation of cyclic GMP and activation of the cGMP-dependent protein kinase I, initiated in the first minutes after administration of oestrogen. The consequences, however, were long lasting, as modulation of Akt and ERK 1/2 activities by NO was responsible for inhibition of E2-triggered cell growth and regulation of oestrogen responsive-element dependent gene transcription. Generation of NO is stimulated by both E2 and growth factors known to contribute to the complex network of intracellular events regulating the biological actions of oestrogen. It is conceivable, therefore, that modulation by NO of E2 early signalling, here described for the first time, has broad significance in regulating cellular responses to the hormone.
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August 2002
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Research Article|
August 15 2002
Nitric oxide regulates oestrogen-activated signalling pathways at multiple levels through cyclic GMP-dependent recruitment of insulin receptor substrate 1
Sestina FALCONE;
Sestina FALCONE
1
∗Department of Pharmacology, University of Milano, 20129 Milano, Italy
†Department of Pharmaco-Biology and Cell Biology, University of Calabria, 87036 Rende, Italy
‡Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milano, Italy
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Loredana MAURO;
Loredana MAURO
1
†Department of Pharmaco-Biology and Cell Biology, University of Calabria, 87036 Rende, Italy
‡Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milano, Italy
2To whom correspondence should be addressed (e-mail clementi.emilio@hsr.it).
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Giacinta de ROSE;
Giacinta de ROSE
†Department of Pharmaco-Biology and Cell Biology, University of Calabria, 87036 Rende, Italy
‡Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milano, Italy
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Clara PAOLUCCI;
Clara PAOLUCCI
†Department of Pharmaco-Biology and Cell Biology, University of Calabria, 87036 Rende, Italy
§Department of Neuroscience, Department of Biological and Technological Research, H San Raffaele Institute, Via Olgettina 58, 20132 Milano, Italy
‡Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milano, Italy
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Clara SCIORATI;
Clara SCIORATI
†Department of Pharmaco-Biology and Cell Biology, University of Calabria, 87036 Rende, Italy
§Department of Neuroscience, Department of Biological and Technological Research, H San Raffaele Institute, Via Olgettina 58, 20132 Milano, Italy
‡Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milano, Italy
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Sebastiano ANDO;
Sebastiano ANDO
1
†Department of Pharmaco-Biology and Cell Biology, University of Calabria, 87036 Rende, Italy
‡Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milano, Italy
2To whom correspondence should be addressed (e-mail clementi.emilio@hsr.it).
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Emilio CLEMENTI
Emilio CLEMENTI
2
†Department of Pharmaco-Biology and Cell Biology, University of Calabria, 87036 Rende, Italy
§Department of Neuroscience, Department of Biological and Technological Research, H San Raffaele Institute, Via Olgettina 58, 20132 Milano, Italy
‡Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section, 20129 Milano, Italy
2To whom correspondence should be addressed (e-mail clementi.emilio@hsr.it).
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Publisher: Portland Press Ltd
Received:
January 03 2002
Revision Received:
April 02 2002
Accepted:
April 29 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (1): 165–173.
Article history
Received:
January 03 2002
Revision Received:
April 02 2002
Accepted:
April 29 2002
Citation
Sestina FALCONE, Loredana MAURO, Giacinta de ROSE, Clara PAOLUCCI, Clara SCIORATI, Sebastiano ANDO, Emilio CLEMENTI; Nitric oxide regulates oestrogen-activated signalling pathways at multiple levels through cyclic GMP-dependent recruitment of insulin receptor substrate 1. Biochem J 15 August 2002; 366 (1): 165–173. doi: https://doi.org/10.1042/bj20020017
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