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In brown adipocytes, adrenergically induced β1-/β3-(Gs)-, α2-(Gi)- and α1-(Gq)-mediated Erk1/2 activation is not mediated via EGF receptor transactivation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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(English)Article in journal (Other academic) Submitted
Abstract [en]

Brown adipose tissue is unusual in utilising the neurotransmitter norepineph- rine to influence cell destiny in ways generally associated with classical growth factors: regulation of cell proliferation, apoptosis, progression of differentiation. These effects are thus mediated through G-protein-coupled receptors; mediation of such stimulation to e.g. Erk1/2 activation is generally accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transac- tivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (α1-adrenoceptor coupled via Gq), clonidine (α2 via Gi) or CL316243 (β3 via Gs) significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of the adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of transactivation. Results with brown adipocytes in more proliferative states were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation or in occur- rence of transactivation. AG1478 action on EGF-stimulated Erk1/2 phos- phorylation showed a sharp concentration-response relationship with an IC50 of approx. 0.3 μM; a minor effect of AG1478 on norepinephrine- stimulated Erk1/2 phosphorylation was clearly nonspecific, occurring suc- cessively and only partially over 3 decades of AG1478 concentrations; cau- tion may therefore be required in interpretation of effects of AG1478 at higher concentrations. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signaling cascades. 

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Other Biological Topics
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-88574OAI: oai:DiVA.org:su-88574DiVA: diva2:612229
Funder
Swedish Cancer Society
Available from: 2013-03-20 Created: 2013-03-20 Last updated: 2013-03-20Bibliographically approved
In thesis
1. cAMP-Regulated Cell Proliferation in Brown Preadipocytes
Open this publication in new window or tab >>cAMP-Regulated Cell Proliferation in Brown Preadipocytes
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

As a prototypical second messenger, cAMP is involved in the regulation of multiple cell functions. cAMP has a well established inhibitory effect on cell proliferation in smooth muscle and epithelial cell types. However, there is accumulating evidence also for stimulatory effect on proliferation, mainly in endocrine cell types.

Mechanisms mediating the cAMP stimulatory effect are not well studied. cAMP, produced via β1-adrenoceptor activation, promotes cell proliferation in brown preadipocytes. Due to the importance of brown adipose tissue in energy metabolism and its implication in the treatment of obesity and type II diabetes, understanding the mechanisms of tissue recruitment has clinical implication for the treatment of these metabolic syndromes.

We found that the Erk1/2 family of MAPK, often involved in regulation of cell proliferation, can be activated in response to the stimulation of G protein-coupled receptors, including adrenergic receptors (α1-, α2-, β1- and β3-Adrenoceptors) and mitogenic lysophosphatidic acid (LPA) in primary cultured brown adipocytes. In contrast to the case e.g. in many immortalized cell lines and various primary cultured cells, EGF receptor transactivation is not employed in Erk1/2 activation by any G protein-coupled receptor tested in brown adipocytes. This suggests that EGF receptor transactivation is not an universal mediation process for GPCR activation of MAPK.

cAMP-activated cell proliferation in brown preadipocytes is mediated through PKA rather than Epac under serum-free conditions. This effect is independent of PI3K/Akt, mTOR or Erk1/2 MAPK pathways. Differential responses to two different MEK inhibitors PD98059 and U0126 suggested the involvement of a pathway sensitive to PD98059, but independent of the Erk1/2 family of MAPK. At the transcriptional level, by combining microarray and RT-qPCR, we have identified eight genes, under the regulation of cAMP, that may be involved in the further mediation of the cAMP effect on cell proliferation.

An understanding of cAMP-induced cell proliferation may be of importance both in metabolic and cancer research.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, Stockholm University, 2013. 78 p.
National Category
Other Biological Topics
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-88393 (URN)978-91-7447-664-4 (ISBN)
Public defence
2013-04-12, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2013-03-21 Created: 2013-03-13 Last updated: 2013-03-22Bibliographically approved

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