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Inhibition of cell proliferation by the Mad1 transcriptional repressor.

Roussel, M F and Ashmun, R A and Sherr, C J and Eisenman, R N and Ayer, D E (1996) Inhibition of cell proliferation by the Mad1 transcriptional repressor. Molecular and cellular biology, 16 (6). pp. 2796-2801. ISSN 0270-7306

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Mad1 is a basic helix-loop-helix-leucine zipper protein that is induced upon differentiation of a number of distinct cell types. Mad1 dimerizes with Max and recognizes the same DNA sequences as do Myc:Max dimers. However, Mad1 and Myc appear to have opposing functions. Myc:Max heterodimers activate transcription while Mad:Max heterodimers repress transcription from the same promoter. In addition Mad1 has been shown to block the oncogenic activity of Myc. Here we show that ectopic expression of Mad1 inhibits the proliferative response of 3T3 cells to signaling through the colony-stimulating factor-1 (CSF-1) receptor. The ability of over-expressed Myc and cyclin D1 to complement the mutant CSF-1 receptor Y809F (containing a Y-to-F mutation at position 809) is also inhibited by Mad1. Cell cycle analysis of proliferating 3T3 cells transfected with Mad1 demonstrates a significant decrease in the fraction of cells in the S and G2/M phases and a concomitant increase in the fraction of G1 phase cells, indicating that Mad1 negatively influences cell cycle progression from the G1 to the S phase. Mutations in Mad1 which inhibit its activity as a transcription repressor also result in loss of Mad1 cell cycle inhibitory activity. Thus, the ability of Mad1 to inhibit cell cycle progression is tightly coupled to its function as a transcriptional repressor.

Item Type: Article or Abstract
Additional Information: This article is freely available in PubMed Central and at the journal's website.
PubMed ID: 8649388
Other ID: PMC231271
Grant Numbers: CA56819, CA20180, CA57138, CA21765
Keywords or MeSH Headings: 3T3 Cells; Animals; Carrier Proteins; Cell Cycle/drug effects/genetics; Cell Cycle Proteins; Cell Division/drug effects/genetics; Cyclin D1; Cyclins/pharmacology; Humans; Macrophage Colony-Stimulating Factor/pharmacology; Mice; Nuclear Proteins/genetics; Oncogene Proteins/pharmacology; Phosphoproteins/genetics; Point Mutation; Proto-Oncogene Proteins c-myc/pharmacology; Receptor, Macrophage Colony-Stimulating Factor/genetics; Repressor Proteins/genetics; Transfection;
Subjects: Molecules > Proteins > Transcription factors
Molecules > Proteins
Cellular and Organismal Processes > Cell Physiology > Cell cycle
Molecules > Genes > Oncogenes
Depositing User: Library Staff
Date Deposited: 26 Nov 2008 19:06
Last Modified: 21 May 2010 23:15

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