A death-promoting role for extracellular signal-regulated kinase
Shougang Zhuang1, Rick G Schnellmann
1Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun St., P. O. Box 250140, Charleston, SC 29425, USA.
Abstract:
Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), which are members of the mitogen-activated protein kinase superfamily, have been well characterized and are known to be involved in cell survival; however, recent evidence suggests that the activation of ERK1/2 also contributes to cell death in some cell types and organs under certain conditions. For example, ERK1/2 is activated in neuronal and renal epithelial cells upon exposure to oxidative stress and toxicants and deprivation of growth factors, and inhibition of the ERK pathway blocks apoptosis. ERK activation also occurs in animal models of ischemia- and trauma-induced brain injury and cisplatin-induced renal injury, and inactivation of ERK reduces the extent of tissue damage. In some studies, ERK has been implicated in apoptotic events upstream of mitochondrial cytochrome c release, whereas other studies have suggested the converse that ERK acts downstream of mitochondrial events and upstream of caspase-3 activation. ERK also can contribute to cell death through the suppression of the antiapoptotic signaling molecule Akt. Here we summarize the evidence and mechanism of ERK-induced apoptosis in both cell culture and in animal models.
Insights
Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) can promote cell death in addition to cell survival. This pathway is activated in various injury models and contributes to apoptosis through multiple mechanisms.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are key regulators in the mitogen-activated protein kinase superfamily.
- While primarily known for roles in cell survival, emerging evidence highlights ERK1/2's involvement in cell death pathways.
Purpose of the Study:
- To review the evidence and elucidate the mechanisms by which ERK1/2 activation contributes to apoptosis.
- To consolidate findings from both cell culture and animal models regarding ERK-induced cell death.
Main Methods:
- Literature review and synthesis of existing research.
- Analysis of studies investigating ERK1/2 activation in response to various cellular stressors (oxidative stress, toxicants, growth factor deprivation).
- Examination of data from animal models of ischemic, traumatic, and toxicant-induced injuries.
Main Results:
- ERK1/2 activation is observed in neuronal and renal cells under stress conditions, and its inhibition can prevent apoptosis.
- ERK pathway activation is implicated in tissue damage in models of brain and kidney injury, with inactivation reducing damage.
- ERK's role in apoptosis is complex, appearing both upstream and downstream of mitochondrial events and capable of suppressing anti-apoptotic signaling via Akt.
Conclusions:
- ERK1/2 plays a dual role in cell fate, capable of inducing apoptosis under specific conditions.
- Understanding ERK-mediated apoptosis is crucial for developing therapeutic strategies against various injuries and diseases.
- Further research is needed to fully delineate the precise molecular mechanisms and contextual regulation of ERK-induced cell death.
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