Abstract
The Ras effector NORE1 is frequently silenced in primary adenocarcinomas, although the significance of this silencing for tumorigenesis is unclear. Here we show that NORE1 induces polyubiquitination and proteasomal degradation of oncoprotein HIPK1 by facilitating its interaction with the Mdm2 E3 ubiquitin ligase. Endogenous HIPK1 is stabilized in Nore1-deficient mouse embryonic fibroblasts, and depletion of HIPK1 in NORE1-silenced lung adenocarcinoma cells inhibits anchorage-independent cell growth and tumour formation in nude mice. These findings indicate that the control of HIPK1 stability by Mdm2-NORE1 has a major effect on cell behaviour, and epigenetic inactivation of NORE1 enables adenocarcinoma formation in vivo through HIPK1 stabilization.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Apoptosis Regulatory Proteins
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Cell Line, Tumor
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Gene Knockdown Techniques
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Humans
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Mice
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Monomeric GTP-Binding Proteins / metabolism*
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Oncogene Proteins / metabolism*
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Polyubiquitin / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism*
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Proteolysis*
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Saccharomyces cerevisiae / metabolism
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Ubiquitination
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ras Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Oncogene Proteins
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RASSF5 protein, human
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Rassf5 protein, mouse
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Polyubiquitin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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HIPK1 protein, human
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Protein Serine-Threonine Kinases
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Monomeric GTP-Binding Proteins
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ras Proteins