Abstract
The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by γ-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins / metabolism
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / metabolism*
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Cell Nucleus / metabolism*
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Checkpoint Kinase 1
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Checkpoint Kinase 2
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DNA Damage*
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DNA-Binding Proteins / metabolism*
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Genes, bcl-2
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Genomic Instability
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Humans
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Immediate-Early Proteins / deficiency
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Immediate-Early Proteins / metabolism*
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Membrane Proteins / metabolism
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Mice
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Mitochondria / metabolism
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Mitosis
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphorylation
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / deficiency
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Tumor Suppressor Proteins / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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IER3 protein, human
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IEX-1 protein, mouse
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Immediate-Early Proteins
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Mcl1 protein, mouse
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Proteins
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Protein Kinases
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Checkpoint Kinase 2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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CHEK1 protein, human
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CHEK2 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases