The Super Anti-apoptotic Factor Bcl-xFNK Constructed by Disturbing Intramolecular Polar Interactions in Rat Bcl-x_L
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概要
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A powerful artificial anti-apoptotic factor will be useful for medical applications of the future therapies for many diseases by prolonging survival of sick cells. For constructing it, we designed the super anti-apoptotic factor by disturbing three intramolecular polar interactions among α-helix structures of Bcl-x_L. The resultant mutant Bcl-x_L, named Bcl-xFNK, was expected to make the pore-forming domain more mobile and flexible than the wild-type. When overexpressed in Jurkat cells, Bcl-xFNK was markedly more potent in prolonging survival following apoptosis-inducing treatment with a kind of cell death cytokines (anti-Fas), a protein kinase inhibitor (staurosporine), cell cycle inhibitors (TN-16,camptothecin, hydroxyurea, and trichostatin A), or oxidative stress (hydrogen peroxide and paraquat) than wild-type Bcl-x_L. Furthermore, the transfectants of bcl-xFNK became more resistant against a calcium ionophore and even a heat treatment than wild-type Bcl-x_L. In addition, Bcl-xFNK showed marked anti-apoptotic activity in Chinese hamster ovary and Jurkat cells deprived of serum. Thus, Bcl-xFNK may be the first mutant generated by site-directed mutagenesis of Bcl-x_L with a gain-of-function phenotype. Interestingly, Bcl-xFNK was found to allow interleukin-3-dependent FDC-P1 to grow without interleukin-3,but not BaF/3. In Bcl-xFNK transfectants of FDC-P1 and Jurkat, the p42/p44 mitogen-activated protein kinase was activated by 2 to 5 times, but not in those of BaF/3 and Chinese hamster ovary. Bcl-xFNK might gain a new function to activate the mitogen-activated protein kinase in a cell-type specific manner. The findings of this study suggest that the central α5-α6 pore-forming region of anti-apoptotic factor Bcl-x_L has a pivotal role in suppressing apoptosis.
- 日本医科大学の論文
- 2001-03-25
著者
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Ohta Shigeo
Department of Biochemistry and Cell Biology, Institute of Development and Aging Science, Graduate Sc
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Ohta Shigeo
Department Of Biochemistry And Cell Biology Institute Of Development And Aging Science Graduate Scho
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Ohta Shigeo
Department Of Biochemistry And Cell Biology Institute Of Gerontology Nippon Medical School
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ASOH Sadamitsu
Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate S
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Ohtsu Takashi
Department of Biochemistry and Cell Biology, Institute of Gerontology, Nippon Medical School
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Ohtsu Takashi
Department Of Biochemistry And Cell Biology Institute Of Gerontology Nippon Medical School:(present
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Asoh Sadamitsu
Department Of Biochemistry And Cell Biology Institute Of Development And Aging Sciences Graduate Of
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