Abstract
Mad1, a member of the Myc/Max/Mad family, suppresses Myc-mediated transcriptional activity by competing with Myc for heterodimerization with its obligatory partner, Max. The expression of Mad1 suppresses Myc-mediated cell proliferation and transformation. The levels of Mad1 protein are generally low in many human cancers, and Mad1 protein has a very short half-life. However, the mechanism that regulates the turnover of Mad1 protein is poorly understood. In this study, we showed that Mad1 is a substrate of p90 ribosomal kinase (RSK) and p70 S6 kinase (S6K). Both RSK and S6K phosphorylate serine 145 of Mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of Mad1 accelerates the ubiquitination and degradation of Mad1 through the 26S proteasome pathway, which in turn promotes the transcriptional activity of Myc. Our study provides a direct link between the growth factor signaling pathways regulated by PI3 kinase/Akt and MAP kinases with Myc-mediated transcription.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Enzyme Activation / drug effects
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Humans
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Insulin / pharmacology
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Mitogens / pharmacology
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Molecular Sequence Data
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation / drug effects
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Phosphoserine / metabolism
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Protein Processing, Post-Translational* / drug effects
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-myc / metabolism*
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Ribosomal Protein S6 Kinases / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism
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Serum
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Substrate Specificity / drug effects
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Thermodynamics
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Transcription, Genetic* / drug effects
Substances
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Cell Cycle Proteins
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Insulin
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MAD1L1 protein, human
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Mitogens
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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Phosphoserine
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases
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Ribosomal Protein S6 Kinases, 90-kDa