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Dual Role of CREB in the regulation of VSMC proliferation : mode of activation determines pro- or anti-mitogenic function

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Hudson, Claire, Kimura, Tomomi, Duggirala, Aparna, Sala-Newby, Graciela B., Newby, Andrew C. and Bond, Mark (2018) Dual Role of CREB in the regulation of VSMC proliferation : mode of activation determines pro- or anti-mitogenic function. Scientific Reports, 8 (1). 4904. doi:10.1038/s41598-018-23199-4 ISSN 2045-2322.

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Official URL: http://doi.org/10.1038/s41598-018-23199-4

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Abstract

Vascular smooth muscle cell (VSMC) proliferation has been implicated in the development of restenosis after angioplasty, vein graft intimal thickening and atherogenesis. We investigated the mechanisms underlying positive and negative regulation of VSMC proliferation by the transcription factor cyclic AMP response element binding protein (CREB). Incubation with the cAMP elevating stimuli, adenosine, prostacyclin mimetics or low levels of forksolin activated CREB without changing CREB phosphorylation on serine-133 but induced nuclear translocation of the CREB co-factors CRTC-2 and CRTC-3. Overexpression of CRTC-2 or -3 significantly increased CREB activity and inhibited VSMC proliferation, whereas CRTC-2/3 silencing inhibited CREB activity and reversed the anti-mitogenic effects of adenosine A2B receptor agonists. By contrast, stimulation with serum or PDGF significantly increased CREB activity, dependent on increased CREB phosphorylation at serine-133 but not on CRTC-2/3 activation. CREB silencing significantly inhibited basal and PDGF induced proliferation. These data demonstrate that cAMP activation of CREB, which is CRTC2/3 dependent and serine-133 independent, is anti-mitogenic. Growth factor activation of CREB, which is serine-133-dependent and CRTC2/3 independent, is pro-mitogenic. Hence, CREB plays a dual role in the regulation of VSMC proliferation with the mode of activation determining its pro- or anti-mitogenic function.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
R Medicine > RD Surgery
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
SWORD Depositor: Library Publications Router
Library of Congress Subject Headings (LCSH): Vascular smooth muscle, Angioplasty, Veins -- Surgery
Journal or Publication Title: Scientific Reports
Publisher: Nature Publishing Group
ISSN: 2045-2322
Official Date: 20 March 2018
Dates:
DateEvent
20 March 2018Published
6 March 2018Accepted
Volume: 8
Number: 1
Article Number: 4904
DOI: 10.1038/s41598-018-23199-4
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 14 May 2018
Date of first compliant Open Access: 14 May 2018
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
PG/14/82/31126 British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
UNSPECIFIEDNational Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272

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