Mad1 Function in Cell Proliferation and Transcriptional Repression Is Antagonized by Cyclin E/CDK2

The transcription factors of the Myc/Max/Mad network play essential roles in the regulation of cellular behavior. Mad1 inhibits cell proliferation by recruiting an mSin3-corepressor complex that contains histone deacetylase activity. Here we demonstrate that Mad1 is a potent inhibitor of the G1 to S...

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Published in:The Journal of biological chemistry 2005-04, Vol.280 (16), p.15489-15492
Main Authors: Rottmann, Sabine, Menkel, Annette R., Bouchard, Caroline, Mertsching, Jürgen, Loidl, Peter, Kremmer, Elisabeth, Eilers, Martin, Lüscher-Firzlaff, Juliane, Lilischkis, Richard, Lüscher, Bernhard
Format: Article
Language:English
Subjects:
3T3-L1 Cells
Animals
CDC2-CDC28 Kinases - metabolism
Cell Cycle Proteins - metabolism
Cell Proliferation
Cyclin E - metabolism
Cyclin-Dependent Kinase 2
Gene Expression Regulation - physiology
Mice
NIH 3T3 Cells
Nuclear Proteins - metabolism
S Phase - physiology
Transcription, Genetic - physiology
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Summary:The transcription factors of the Myc/Max/Mad network play essential roles in the regulation of cellular behavior. Mad1 inhibits cell proliferation by recruiting an mSin3-corepressor complex that contains histone deacetylase activity. Here we demonstrate that Mad1 is a potent inhibitor of the G1 to S phase transition, a function that requires Mad1 to heterodimerize with Max and to bind to the corepressor complex. Cyclin E/CDK2, but not cyclin D and cyclin A complexes, fully restored S phase progression. In addition inhibition of colony formation and gene repression by Mad1 were also efficiently antagonized by cyclin E/CDK2. This was the result of cyclin E/CDK2 interfering with the interaction of Mad1 with HDAC1 and reducing HDAC activity. Our findings define a novel interplay between the cell cycle regulator cyclin E/CDK2 and Mad1 and its associated repressor complex and suggests an additional mechanism how cyclin E/CDK2 affects the G1 to S phase transition.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C400611200