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Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation.

Hurlin, P J and Quéva, C and Koskinen, P J and Steingrímsson, E and Ayer, D E and Copeland, N G and Jenkins, N A and Eisenman, R N (1995) Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation. The EMBO journal, 14 (22). pp. 5646-5659. ISSN 0261-4189

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The basic helix-loop-helix-leucine zipper (bHLHZip) protein Max associates with members of the Myc family, as well as with the related proteins Mad (Mad1) and Mxi1. Whereas both Myc:Max and Mad:Max heterodimers bind related E-box sequences, Myc:Max activates transcription and promotes proliferation while Mad:Max represses transcription and suppresses Myc dependent transformation. Here we report the identification and characterization of two novel Mad1- and Mxi1-related proteins, Mad3 and Mad4. Mad3 and Mad4 interact with both Max and mSin3 and repress transcription from a promoter containing CACGTG binding sites. Using a rat embryo fibroblast transformation assay, we show that both Mad3 and Mad4 inhibit c-Myc dependent cell transformation. An examination of the expression patterns of all mad genes during murine embryogenesis reveals that mad1, mad3 and mad4 are expressed primarily in growth-arrested differentiating cells. mxi1 is also expressed in differentiating cells, but is co-expressed with either c-myc, N-myc, or both in proliferating cells of the developing central nervous system and the epidermis. In the developing central nervous system and epidermis, downregulation of myc genes occurs concomitant with upregulation of mad family genes. These expression patterns, together with the demonstrated ability of Mad family proteins to interfere with the proliferation promoting activities of Myc, suggest that the regulated expression of Myc and Mad family proteins function in a concerted fashion to regulate cell growth in differentiating tissues.

Item Type: Article
Additional Information: This article is freely available in PubMed Central. No URL is available at the journal's website.
PubMed ID: 8521822
PMCID: PMC394680
Grant Numbers: ROlCA57138, NOI-CO-46000
Keywords or MeSH Headings: 3T3 Cells; Amino Acid Sequence; Animals; Base Sequence; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Basic Helix-Loop-Helix Transcription Factors; Basic-Leucine Zipper Transcription Factors; Cell Differentiation; Cell Transformation, Neoplastic/genetics; Cells, Cultured; Chromosome Mapping; DNA-Binding Proteins/genetics/metabolism; Epidermis/cytology/embryology/metabolism; Genes, myc; I-kappa B Proteins; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Protein Binding; Proto-Oncogene Proteins c-myc/genetics/metabolism; Rats; Repressor Proteins/genetics/metabolism; Spinal Cord/cytology/embryology/metabolism; Transcription Factors; Transcription, Genetic; Tumor Suppressor Proteins;
Subjects: Molecules > Proteins > Transcription factors
Molecules > Genes > Oncogenes
Cellular and Organismal Processes > Cell Physiology > Cell differentiation
Cellular and Organismal Processes > Genetic processes > Transcription
Depositing User: Library Staff
Date Deposited: 26 Nov 2008 21:01
Last Modified: 21 May 2010 23:15

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