Abstract
p53 family members with a transactivation (TA) domain induce cell cycle arrest and promote apoptosis. However, DeltaNp63 isotypes lacking the TA-domain promote cell proliferation and tumorigenesis in vitro and in vgammavo. Although p53, TAp63 or TAp73 are stabilized upon DNA damage, we found that the genotoxic stress agents induced a dramatic decrease and phosphorylation of DeltaNp63alpha in squamous cell carcinoma cells. Further work revealed that RACK1 physically associated with the p63alpha C-terminal domain through its WD40 domain. However, stratifin binds with phosphorylated DeltaNp63alpha in response to cisplatin. Upon DNA damage induced by cisplatin, stratifin mediated a nuclear export of DeltaNp63alpha into cytoplasm and then RACK1 targeted latter into a proteasome degradation pathway possibly serving as an E3 ubiquitin ligase. Moreover, siRNA knockdown of both stratifin and RACK1 inhibited a nuclear export and protein degradation of DeltaNp63alpha, respectively. Our data suggest that modification and down regulation of DeltaNp63alpha is one of the major determinants of the cellular response to DNA damage in human head and neck cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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14-3-3 Proteins
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Biomarkers, Tumor / metabolism*
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Carcinoma, Squamous Cell / genetics
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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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Cisplatin / pharmacology
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DNA Damage*
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DNA-Binding Proteins
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Exonucleases / metabolism*
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Exoribonucleases
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GTP-Binding Proteins / chemistry
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GTP-Binding Proteins / metabolism*
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Genes, Tumor Suppressor
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Head and Neck Neoplasms / genetics
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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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Keratinocytes / drug effects
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Kinetics
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / metabolism*
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Phosphoproteins / chemistry
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Phosphoproteins / metabolism*
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Phosphorylation / drug effects
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Proteasome Endopeptidase Complex / metabolism*
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Protein Binding
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Protein Isoforms
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Protein Processing, Post-Translational
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Protein Structure, Tertiary
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Protein Transport
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RNA Interference
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Receptors for Activated C Kinase
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Receptors, Cell Surface / chemistry
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Receptors, Cell Surface / metabolism*
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Recombinant Fusion Proteins
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Trans-Activators / chemistry
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Trans-Activators / metabolism*
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Transcription Factors
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Tumor Suppressor Proteins
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Two-Hybrid System Techniques
Substances
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14-3-3 Proteins
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Biomarkers, Tumor
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DNA-Binding Proteins
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Neoplasm Proteins
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Phosphoproteins
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Protein Isoforms
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RACK1 protein, human
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Receptors for Activated C Kinase
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Receptors, Cell Surface
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Recombinant Fusion Proteins
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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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Exonucleases
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Exoribonucleases
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SFN protein, human
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Proteasome Endopeptidase Complex
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GTP-Binding Proteins
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Cisplatin