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Identifying novel genes involved in cAMP- induced cell proliferation of brown preadi- pocytes
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Norepinephrine, through the second messenger cAMP, stimulates cell prolif- eration in a variety of cell types including brown preadipocytes. However, the cell signalling pathway mediating the cAMP mitogenic effect is poorly established, especially in physiologically relevant systems. A change in tran- scriptional profile due to the activation of specific transcription factors is an important part of intracellular signalling activated by various extracellular stimulants. In the present study, we have used brown preadipocytes as a model system to investigate novel genes that are involved in cAMP-induced cell growth. Based on data from a genome-wide microarray study, 18 genes upregulated by NE in brown preadipocyte were selected for further study. These genes were later confirmed with RT-qPCR to be upregulated by both norepinephrine and forskolin, indicating that they are truly under the positive regulation of cAMP. We therefore suggest that these genes, namely: Ado- ra2b, Arhgap8, Fgf18, Gpr133, Prr5, Tmem37, Twist2 and Ube2s, may be candidates involved in cAMP-stimulated cell proliferation. 

National Category
Other Biological Topics
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-88577OAI: oai:DiVA.org:su-88577DiVA: diva2:612234
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)
Opponent
Supervisors
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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