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14-3-3 proteins block apoptosis and differentially regulate MAPK cascades.
H Xing1, S Zhang, C Weinheimer
1Departments of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MO 63110, USA.
The EMBO Journal
|February 2, 2000
Summary
Mammalian 14-3-3 proteins are crucial for inhibiting apoptosis. Disrupting their function in cells and animals led to increased cell death and severe cardiac dysfunction, highlighting their essential role in cell survival.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- 14-3-3 proteins are dimeric phosphoserine-binding proteins involved in signal transduction and checkpoint control.
- Their precise role in regulating apoptosis remains incompletely understood.
Purpose of the Study:
- To investigate the function of 14-3-3 proteins in regulating apoptosis and cellular stress responses.
- To elucidate the role of 14-3-3 proteins in cardiac tissue under stress.
Main Methods:
- Utilized dominant-negative mutant forms of 14-3-3 (DN-14-3-3zeta and DN-14-3-3eta) in cultured cells and transgenic animal models.
- Assessed mitogen-activated protein kinase (MAPK) pathway activation (ERK, JNK1, p38 MAPK) and apoptosis levels.
- Examined cardiac function and survival in mice subjected to pressure overload.
Main Results:
- Inhibition of 14-3-3zeta function in fibroblasts altered MAPK activation and significantly increased UVC-induced apoptosis, which was p38 MAPK-dependent.
- Targeted expression of DN-14-3-3eta in murine cardiac tissue elevated JNK1 and p38 MAPK activity.
- DN-14-3-3eta expression impaired cardiac compensation to pressure overload, leading to increased mortality, dilated cardiomyopathy, and cardiomyocyte apoptosis.
Conclusions:
- Mammalian 14-3-3 proteins play a critical role in actively inhibiting apoptosis.
- Disruption of 14-3-3 function sensitizes cells to apoptotic stimuli and impairs cardiac stress response.
- 14-3-3 proteins are essential for maintaining cardiac homeostasis and preventing cell death under stress.