Abstract
Only a few p53 regulators have been shown to participate in the selective control of p53-mediated cell cycle arrest or apoptosis. How p53-mediated apoptosis is negatively regulated remains largely unclear. Here we report that Apak (ATM and p53-associated KZNF protein), a Krüppel-associated box (KRAB)-type zinc-finger protein, binds directly to p53 in unstressed cells, specifically downregulates pro-apoptotic genes, and suppresses p53-mediated apoptosis by recruiting KRAB-box-associated protein (KAP)-1 and histone deacetylase 1 (HDAC1) to attenuate the acetylation of p53. Apak inhibits p53 activity by interacting with ATM, a previously identified p53 activator. In response to stress, Apak is phosphorylated by ATM and dissociates from p53, resulting in activation of p53 and induction of apoptosis. These findings revealed Apak to be a negative regulator of p53-mediated apoptosis and showed the dual role of ATM in p53 regulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Amino Acid Sequence
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / physiology*
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Ataxia Telangiectasia Mutated Proteins
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Binding Sites / physiology
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Carrier Proteins / chemistry
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Carrier Proteins / physiology*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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DNA Damage / physiology
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DNA-Binding Proteins / metabolism
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Gene Expression / genetics
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Histone Deacetylase 1
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Histone Deacetylases / metabolism
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Humans
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Models, Biological
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Molecular Sequence Data
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Phosphorylation
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Protein Binding / physiology
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Protein Interaction Domains and Motifs / physiology
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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Repressor Proteins / metabolism
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Serine / metabolism
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Tripartite Motif-Containing Protein 28
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / metabolism
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Two-Hybrid System Techniques
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Zinc Fingers / physiology
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bcl-2-Associated X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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Repressor Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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ZNF420 protein, human
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bcl-2-Associated X Protein
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Serine
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TRIM28 protein, human
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Tripartite Motif-Containing Protein 28
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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HDAC1 protein, human
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Histone Deacetylase 1
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Histone Deacetylases