Abstract
NOXA is a BH3-only protein whose expression is induced by certain p53-depenent or independent apoptotic stimuli. Both NOXA and Bim are avid binders of Mcl-1, but a functional linkage between these BH3-only proteins has not yet been reported. In this study, we demonstrate that Mcl-1 binding of endogenously induced NOXA interferes with the ability of Mcl-1 to efficiently sequester endogenous Bim, as Bim is displaced from its complex with Mcl-1. Induced NOXA significantly enhances the UV sensitivity of cells, and the ensuing mitochondrial depolarization is entirely abrogated by Bim knockdown. These results demonstrate a Mcl-1-mediated cross-talk between endogenous NOXA and Bim that occurs upstream of the Bak/Bax-dependent execution of UV-induced mitochondrial depolarization. The current findings demonstrate that the mitochondrial response to an induced expression of NOXA is executed by endogenous Bim and suggest a plausible mechanism for the observed NOXA-Bim linkage.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Apoptosis Regulatory Proteins / biosynthesis*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis* / genetics
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Apoptosis* / radiation effects
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Bcl-2-Like Protein 11
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HeLa Cells
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Humans
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Jurkat Cells
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Membrane Proteins / biosynthesis*
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Membrane Proteins / genetics
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Mitochondria / genetics
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Mitochondria / metabolism*
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Protein Binding / genetics
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Protein Binding / radiation effects
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Ultraviolet Rays
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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BAK1 protein, human
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BAX protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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PMAIP1 protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein