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Repression of c-fos and c-jun gene expression is not part of AT2 receptor coupled signal transduction
U M Steckelings1, S P Bottari, M Stoll
1Department of Pharmacology, Christian-Albrechts-Universität, Kiel, Germany.
Abstract:
The signal transduction mechanism coupled to angiotensin AT2 receptors is still a matter of debate. Based on the findings that AT2 receptor stimulation causes inhibition of proliferation, and that other antiproliferative agents such as transforming growth factor-beta, retinoic acid, and MyoD act via repression of immediate early gene (IEG) expression, this study was aimed at elucidating whether downregulation of IEG expression is also part of the AT2 receptor coupled signaling mechanism. Stimulation of angiotensin AT2 receptors in the rat pheochromocytoma cell line PC12 W following pretreatment with growth factors was able to counteract growth factor induced proliferation but not to repress growth factor induced c-fos and c-jun expression; neither did AT2 receptor stimulation cause an induction of c-fos expression. We conclude that, in contrast to other growth-inhibiting agents, the antiproliferative effect of angiotensin II via the AT2 receptor is not mediated by repression of the immediate early genes c-fos and c-jun.
Insights
Angiotensin AT2 receptor stimulation inhibits cell proliferation but does not repress immediate early gene expression, unlike other growth inhibitors. This finding clarifies the AT2 receptor signaling pathway.
Area of Science:
- Molecular Biology
- Cell Signaling
- Pharmacology
Background:
- The signal transduction pathways for angiotensin AT2 receptors are not fully understood.
- Known antiproliferative agents like TGF-β, retinoic acid, and MyoD function by downregulating immediate early gene (IEG) expression.
Purpose of the Study:
- To investigate if the downregulation of IEG expression is involved in the signaling mechanism of angiotensin AT2 receptors.
- To determine if angiotensin II's antiproliferative effect via AT2 receptors involves IEG repression.
Main Methods:
- Utilized the rat pheochromocytoma cell line PC12 W.
- Stimulated angiotensin AT2 receptors after pretreatment with growth factors.
- Monitored cell proliferation and the expression of immediate early genes (c-fos and c-jun).
Main Results:
- Angiotensin AT2 receptor stimulation counteracted growth factor-induced proliferation in PC12 W cells.
- AT2 receptor stimulation did not repress growth factor-induced c-fos and c-jun expression.
- AT2 receptor stimulation did not induce c-fos expression.
Conclusions:
- The antiproliferative effect of angiotensin II mediated by the AT2 receptor is not achieved through the repression of immediate early genes c-fos and c-jun.
- This distinguishes AT2 receptor signaling from other known antiproliferative mechanisms.