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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
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Official URL: http://doi.org/10.1038/s41598-018-23199-4
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 | |||||||||
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| Subjects: | Q Science > QP Physiology R Medicine > RD Surgery |
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| Divisions: | Faculty of 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: |
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| 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 | |||||||||
| RIOXX Funder/Project Grant: |
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