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Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis
Z Xia1, M Dickens, J Raingeaud
1Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.
Insights
Mitogen-activated protein kinase pathways regulate neuronal cell death. Stress-activated JNK and p38 pathways promote apoptosis, while ERK pathways inhibit it, influencing neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Apoptosis is crucial for neuronal development.
- Dysregulation of apoptosis is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the role of mitogen-activated protein (MAP) kinase pathways in neuronal apoptosis.
- To elucidate the molecular mechanisms governing neuronal cell death.
Main Methods:
- Used rat PC-12 pheochromocytoma cells.
- Withdrew nerve growth factor (NGF) to induce apoptosis.
- Examined the activation/inhibition of ERK, JNK, and p38 MAP kinases.
- Utilized dominant-interfering and constitutively activated signaling pathway components.
Main Results:
- NGF withdrawal caused sustained activation of JNK and p38.
- NGF withdrawal led to inhibition of ERK.
- Activation of JNK/p38 and inhibition of ERK were critical for apoptosis induction.
Conclusions:
- The balance between ERK and JNK/p38 signaling pathways determines neuronal survival or apoptosis.
- MAP kinase signaling is a key regulator of neuronal cell death.
- Understanding these pathways may offer insights into neurodegenerative disorders.