Abstract
We demonstrate that deltaNp63alpha is an essential survival factor in head and neck squamous cell carcinoma (HNSCC) through its ability to suppress p73-dependent apoptosis. Inhibition of endogenous p63 expression by RNAi induces apoptosis selectively in HNSCC cells that overexpress deltaNp63alpha. Knockdown of p63 induces the proapoptotic bcl-2 family members Puma and Noxa, and both their induction and subsequent cell death are p53 independent but require transactivating isoforms of p73. Inhibition of p73-dependent transcription by deltaNp63alpha involves both direct promoter binding and physical interaction with p73. In HNSCC cells lacking endogenous deltaNp63alpha expression, bcl-2 is instead upregulated and can suppress p73-mediated death. Together, these data define a pathway whereby deltaNp63alpha promotes survival in squamous epithelial malignancy by repressing a p73-dependent proapoptotic transcriptional program.
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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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cell Survival*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Genes, Tumor Suppressor / physiology*
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Genes, bcl-2
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Genes, p53
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Head and Neck Neoplasms / metabolism*
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Head and Neck Neoplasms / pathology
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Humans
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / physiology*
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Promoter Regions, Genetic
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Protein Binding
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Protein Isoforms / genetics
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Protein Isoforms / physiology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / physiology*
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Transcription Factors
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Transcriptional Activation
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Tumor Protein p73
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Tumor Suppressor Proteins
Substances
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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DNA-Binding Proteins
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Nuclear Proteins
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PMAIP1 protein, human
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Phosphoproteins
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Protein Isoforms
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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TP63 protein, human
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TP73 protein, human
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Trans-Activators
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Transcription Factors
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Tumor Protein p73
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Tumor Suppressor Proteins