Abstract
beta-catenin is a multifunctional protein, acting both as a structural component of the cell adhesion machinery and as a transducer of extracellular signals. Deregulated beta-catenin protein expression, due to mutations in the beta-catenin gene itself or in its upstream regulator, the adenomatous polyposis coli (APC) gene, is prevalent in colorectal cancer and in several other tumor types, and attests to the potential oncogenic activity of this protein. Increased expression of beta-catenin is an early event in colorectal carcinogenesis, and is usually followed by a later mutational inactivation of the p53 tumor suppressor. To examine whether these two key steps in carcinogenesis are interrelated, we studied the effect of excess beta-catenin on p53. We report here that overexpression of beta-catenin results in accumulation of p53, apparently through interference with its proteolytic degradation. This effect involves both Mdm2-dependent and -independent p53 degradation pathways, and is accompanied by augmented transcriptional activity of p53 in the affected cells. Increased p53 activity may provide a safeguard against oncogenic deregulation of beta-catenin, and thus impose a pressure for mutational inactivation of p53 during the later stages of tumor progression.
Publication types
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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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Adaptor Proteins, Signal Transducing
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Animals
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Cell Line
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Cell Nucleus / metabolism
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Colorectal Neoplasms / etiology
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Colorectal Neoplasms / genetics
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Cysteine Proteinase Inhibitors / pharmacology
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Cytoskeletal Proteins / physiology
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Desmoplakins
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Dishevelled Proteins
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Gene Expression*
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Humans
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Leupeptins / pharmacology
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Mice
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Mutation
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Nuclear Proteins*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-mdm2
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction
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Solubility
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Trans-Activators*
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Transcription, Genetic / genetics*
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Transfection
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Up-Regulation* / drug effects
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beta Catenin
Substances
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Adaptor Proteins, Signal Transducing
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cysteine Proteinase Inhibitors
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Cytoskeletal Proteins
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Desmoplakins
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Dishevelled Proteins
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Leupeptins
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Nuclear Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Trans-Activators
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Tumor Suppressor Protein p53
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beta Catenin
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde