Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1.

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.
Mesh Terms:
Amino Acid Sequence, Amino Acid Substitution, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Enzyme Activation, Humans, Insulin, Mitogens, Molecular Sequence Data, Nuclear Proteins, Phosphatidylinositol 3-Kinases, Phosphorylation, Phosphoserine, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, Ribosomal Protein S6 Kinases, Ribosomal Protein S6 Kinases, 90-kDa, Serum, Substrate Specificity, Thermodynamics, Transcription, Genetic
Proc. Natl. Acad. Sci. U.S.A.
Date: May. 06, 2008
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