Abstract
Cisplatin remains the most important chemotherapeutic agent for patients with human head and neck cancer. However, tumor cells often develop resistance to cisplatin-induced apoptosis. We previously found that head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin display a marked ATM-induced phosphorylation of DeltaNp63alpha. However, the mutated Np63-S385G failed to undergo phosphorylation by ATM kinase. We used HNSCC cell lines expressing the wild type DeltaNp63alpha or mutated DeltaNp63alpha-S385G to determine the effect of S385G mutation on the DeltaNp63alpha transcriptional activity and protein-protein interactions. The S385G mutation in DeltaNp63alpha dramatically abolished the upregulation/downregulation of downstream gene targets and the binding of DeltaNp63alpha-S385G to certain promoters. In contrast to the non-phosphorylated DeltaNp63alpha-S385G, the phospho-DeltaNp63alpha forms protein-protein complexes with NF-YA transcription factor and regulates the transcription of DDIT3 gene implicated in the programmed cell death of HNSCC cells upon cisplatin exposure. We suggest that the transcriptional activation of DeltaNp63alpha through its phosphorylation by ATM kinase in HNSCC cells exposed to cisplatin is a critical step in the subsequent sensitivity of certain human head and neck cancers to platinum therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Ataxia Telangiectasia Mutated Proteins
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CCAAT-Binding Factor / metabolism*
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism
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Cell Cycle Proteins / metabolism
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Cisplatin / pharmacology*
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Gene Expression Regulation, Neoplastic
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Head and Neck Neoplasms / drug therapy
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Head and Neck Neoplasms / genetics*
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Head and Neck Neoplasms / metabolism
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Humans
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Mutation
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Phosphorylation
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Protein Interaction Domains and Motifs
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Protein Serine-Threonine Kinases / metabolism
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RNA, Messenger / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism*
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Transcription Factors
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Transcription, Genetic
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Up-Regulation
Substances
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Antineoplastic Agents
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CCAAT-Binding Factor
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Cell Cycle Proteins
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DDIT3 protein, human
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DNA-Binding Proteins
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NFYA protein, human
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RNA, Messenger
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TP63 protein, human
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Proteins
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Transcription Factor CHOP
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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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Cisplatin