期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 18, 页码 6584-6589出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802785105
关键词
phosphorylation; RSK; S6K1; ubiquitination; proliferation
资金
- NIA NIH HHS [5 R37 AG012859, R37 AG012859] Funding Source: Medline
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.
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