The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax

In response to DNA damage and genotoxic stress, the p53 tumor suppressor triggers either cell cycle arrest or apoptosis. The G(2) arrest after damage is, in part, mediated by the p53 target, 14-3-3final sigma (final sigma). Colorectal tumor cells lacking final sigma are exquisitely sensitive to DNA...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-11, Vol.276 (48), p.45201-45206
Main Authors: Samuel, T, Weber, H O, Rauch, P, Verdoodt, B, Eppel, J T, McShea, A, Hermeking, H, Funk, J O
Format: Article
Language:English
Subjects:
14-3-3 Proteins
Adenoviridae - genetics
Apoptosis
bcl-2-Associated X Protein
Caspase 3
Caspases - metabolism
Cell Cycle
Cell Line
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - metabolism
Cytochrome c Group - metabolism
Cytoplasm - metabolism
Cytosol - metabolism
Doxorubicin - pharmacology
Enzyme Activation
G2 Phase
Humans
Microscopy, Fluorescence
Mitochondria - metabolism
Mitosis
Phenotype
Precipitin Tests
Protein Binding
Protein Transport
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2
Signal Transduction
Tumor Suppressor Protein p53 - metabolism
Tyrosine 3-Monooxygenase - chemistry
Tyrosine 3-Monooxygenase - physiology
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Summary:In response to DNA damage and genotoxic stress, the p53 tumor suppressor triggers either cell cycle arrest or apoptosis. The G(2) arrest after damage is, in part, mediated by the p53 target, 14-3-3final sigma (final sigma). Colorectal tumor cells lacking final sigma are exquisitely sensitive to DNA damage. Here we analyzed the mechanism of this sensitivity in final sigma(-/-) as compared with final sigma(+/+) human colorectal tumor cells. Exposure to adriamycin resulted in rapid apoptosis only in final sigma(-/-) cells. This was further characterized by caspase-3 activation, p21(CIP1) cleavage, and CDK2 activation. Moreover, Bax was rapidly translocated out of the cytoplasm, and cytochrome c was released in final sigma(-/-) cells. Transient adenovirus-mediated reconstitution of final sigma in the final sigma(-/-) cells led to effective rescue of this phenotype and protected cells against apoptosis. The association of final sigma, Bax, and CDK1 in protein complexes may be the basis for this antiapoptotic mechanism. In conclusion, final sigma not only enforces the p53-dependent G(2) arrest but also delays the apoptotic signal transduction.
ISSN:0021-9258