Abstract
A new p53 family member, p73, and its isoform DeltaNp73 are increasingly recognized in cancer research as important players in tumorigenesis, as well as in chemotherapeutic drug sensitivity. Despite substantial structural similarities to p53, accumulating evidence suggests that p53 and p73 may play different roles in human tumorigenesis. In this study, we have investigated the role of p73 and DeltaNp73 in upper gastrointestinal tumorigenesis. Our results indicate that p73 and DeltaNp73 are frequently overexpressed in >60% of primary adenocarcinomas of the stomach and esophagus. We have demonstrated that this overexpression can lead to the suppression of p73 transcriptional and apoptotic activity in gastrointestinal cells. Moreover, it induces beta-catenin up-regulation and T-cell factor/lymphocyte enhancement factor-dependent transcription. Wild-type p53, but not mutant p53, can inhibit this effect. Our results demonstrate a novel mechanism for activation of beta-catenin in gastrointestinal tumors and support the concept that overexpression of p73 isoforms can play an important role in tumorigenesis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Apoptosis / physiology
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cytoskeletal Proteins / biosynthesis
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Cytoskeletal Proteins / genetics
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Esophageal Neoplasms / genetics
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Esophageal Neoplasms / metabolism
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Esophageal Neoplasms / pathology
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Gene Expression Regulation, Neoplastic
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Genes, Tumor Suppressor
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Humans
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Protein Isoforms
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Stomach Neoplasms / pathology
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TCF Transcription Factors
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcriptional Activation
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Transfection
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Tumor Protein p73
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Tumor Suppressor Proteins
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Up-Regulation
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beta Catenin
Substances
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CTNNB1 protein, human
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Nuclear Proteins
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Protein Isoforms
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RNA, Messenger
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TCF Transcription Factors
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TCF7L2 protein, human
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TP73 protein, human
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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Tumor Protein p73
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Tumor Suppressor Proteins
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beta Catenin
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delta Np73 protein, human