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PMID: 8521822 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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 ·Vol. 14 ·No. 22 ·1995-11-15 ·Pages 5646-59

Hurlin PJ, Quéva C, Koskinen PJ, Steingrímsson E, Ayer DE, Copeland NG, Jenkins NA, Eisenman RN

Abstract

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.

MeSH Terms
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 Epidermal Cells Epidermis/embryology,metabolism Genes, myc I-kappa B Proteins Mice Mice, Inbred C57BL Molecular Sequence Data NF-KappaB Inhibitor alpha 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
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Basic Helix-Loop-Helix Transcription Factors Basic-Leucine Zipper Transcription Factors DNA-Binding Proteins I-kappa B Proteins MXI1 protein, human Mad4 protein, mouse Max protein, rat Mxi1 protein, mouse Mxi1 protein, rat Myc associated factor X NFKBIA protein, human Nfkbia protein, mouse Nfkbia protein, rat Proto-Oncogene Proteins c-myc Repressor Proteins Transcription Factors Tumor Suppressor Proteins Max protein, mouse NF-KappaB Inhibitor alpha
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Hurlin P J
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
Quéva C
Koskinen P J
Steingrímsson E
Ayer D E
Copeland N G
Jenkins N A
Eisenman R N
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1995-11-15
Pages
5646-59
Language
English
Region
England
NLM ID
8208664
PMCID
PMC394680
Subset
IM
Grants
NCI NIH HHS · N01-CO-46000 · United States
NCI NIH HHS · R01CA57138 · United States
Databases
GENBANK
U32394, U32395
Corrections
ErratumIn
PMID: 8617250
External Links
PubMed source PMC Full Text View journal details
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