Abstract
The c-Myc oncoprotein is strongly induced during the G0 to S-phase transition and is an important regulator of cell cycle entry. In contrast to c-Myc, the putative Myc antagonist Mnt is maintained at a constant level during cell cycle entry. Mnt and Myc require interaction with Max for specific DNA binding at E-box sites, but have opposing transcriptional activities. Here, we show that c-Myc induction during cell cycle entry leads to a transient decrease in Mnt-Max complexes and a transient switch in the ratio of Mnt-Max to c-Myc-Max on shared target genes. Mnt overexpression suppressed cell cycle entry and cell proliferation, suggesting that the ratio of Mnt-Max to c-Myc-Max is critical for cell cycle entry. Furthermore, simultaneous Cre-Lox mediated deletion of Mnt and c-Myc in mouse embryo fibroblasts rescued the cell cycle entry and proliferative block caused by c-Myc ablation alone. These results demonstrate that Mnt-Myc antagonism plays a fundamental role in regulating cell cycle entry and proliferation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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Cell Cycle / physiology*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Transformed
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Cell Proliferation
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation / physiology
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Fibroblasts / metabolism
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Gene Deletion
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Gene Expression Regulation / physiology
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Gene Silencing / physiology
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Gene Targeting
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Macromolecular Substances / metabolism
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Mice
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Mice, Knockout
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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Cell Cycle Proteins
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DNA-Binding Proteins
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Macromolecular Substances
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Mnt protein, mouse
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Myc associated factor X
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Myc protein, mouse
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Proto-Oncogene Proteins c-myc
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Repressor Proteins
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Transcription Factors
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Max protein, mouse