Related Experiment Videos
Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and
M Horiuchi1, W Hayashida, T Kambe
1Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Abstract:
We examined the cellular and signaling mechanism of angiotensin II (Ang II) type 2 (AT2) receptor-induced apoptosis in PC12W (rat pheochromocytoma cell line) cells that express abundant AT2 receptor but not Ang II type 1 receptor. In these cells, nerve growth factor (NGF) inhibited the internucleosomal DNA fragmentation induced by serum depletion, whereas Ang II antagonized this NGF cell survival action and induced apoptosis. We studied the mechanism of NGF and AT2 receptor interaction on apoptosis by examining their effects on the survival factor Bcl-2. AT2 receptor activation did affect intracellular Bcl-2 protein levels. Bcl-2 phosphorylation was stimulated by NGF, whereas AT2 receptor activation blocked this NGF effect. Pretreatment with antisense oligonucleotide of mitogen-activated protein (MAP) kinase phosphatase-1 enhanced the effects of NGF on MAP kinase activation and Bcl-2 phosphorylation but attenuated the inhibitory effects of AT2 receptor on MAP kinase, Bcl-2 phosphorylation, and apoptosis. Taken together, these results suggest that MAP kinase plays a critical role in inhibiting apoptosis by phosphorylating Bcl-2. The AT2 receptor inhibits MAP kinase activation, resulting in the inactivation of Bcl-2 and the induction of apoptosis.
Insights
Angiotensin II (Ang II) type 2 (AT2) receptor activation induces apoptosis by inhibiting the survival pathway. This involves blocking mitogen-activated protein (MAP) kinase and Bcl-2 phosphorylation, crucial for cell survival.
Area of Science:
- Cellular and Molecular Neuroscience
- Receptor Signaling Pathways
- Apoptosis Mechanisms
Background:
- Nerve growth factor (NGF) promotes cell survival in PC12W cells.
- Angiotensin II (Ang II) type 2 (AT2) receptor activation antagonizes NGF's survival effects.
- The AT2 receptor's role in apoptosis induction requires elucidation.
Purpose of the Study:
- To investigate the cellular and signaling mechanisms of AT2 receptor-induced apoptosis.
- To explore the interaction between NGF and AT2 receptor signaling in apoptosis.
- To determine the role of mitogen-activated protein (MAP) kinase and Bcl-2 in this process.
Main Methods:
- Utilized PC12W cells expressing AT2 receptors but lacking Ang II type 1 receptors.
- Examined internucleosomal DNA fragmentation as an apoptosis marker.
- Assessed intracellular Bcl-2 protein levels and phosphorylation.
- Investigated the effects of MAP kinase phosphatase-1 modulation.
Main Results:
- NGF inhibited serum depletion-induced apoptosis; Ang II antagonized NGF and induced apoptosis.
- AT2 receptor activation blocked NGF-stimulated Bcl-2 phosphorylation.
- MAP kinase activation and Bcl-2 phosphorylation were critical for NGF-mediated survival.
- AT2 receptor activation inhibited MAP kinase, leading to Bcl-2 inactivation and apoptosis.
Conclusions:
- MAP kinase plays a vital role in inhibiting apoptosis through Bcl-2 phosphorylation.
- AT2 receptor activation inhibits MAP kinase signaling, inactivating Bcl-2 and inducing apoptosis.
- This study elucidates a novel signaling pathway for AT2 receptor-mediated apoptosis.