14-3-3 proteins block apoptosis and differentially regulate MAPK cascades.
14-3-3 family members are dimeric phosphoserine-binding proteins that participate in signal transduction and checkpoint control pathways. In this work, dominant-negative mutant forms of 14-3-3 were used to disrupt 14-3-3 function in cultured cells and in transgenic animals. Transfection of cultured fibroblasts with the R56A and R60A double mutant form of 14-3-3zeta (DN-14-3-3zeta) inhibited serum-stimulated ERK MAPK activation, but increased the basal activation of JNK1 and p38 MAPK. Fibroblasts transfected with DN-14-3-3zeta exhibited markedly increased apoptosis in response to UVC irradiation that was blocked by pre-treatment with a p38 MAPK inhibitor, SB202190. Targeted expression of DN-14-3-3eta to murine postnatal cardiac tissue increased the basal activation of JNK1 and p38 MAPK, and affected the ability of mice to compensate for pressure overload, which resulted in increased mortality, dilated cardiomyopathy and massive cardiomyocyte apoptosis. These results demonstrate that a primary function of mammalian 14-3-3 proteins is to inhibit apoptosis.
Xing
H
H
Departments of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MO 63110, USA.
Zhang
S
S
Weinheimer
C
C
Kovacs
A
A
Muslin
A J
AJ
D048948:14-3-3 Proteins; D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D007093:Imidazoles / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D048948:14-3-3 Proteins; D016895:Culture Media, Serum-Free; D007093:Imidazoles; D011506:Proteins; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D014446:Tyrosine 3-Monooxygenase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole