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PMID: 9451002 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Targeted disruption of the MYC antagonist MAD1 inhibits cell cycle exit during granulocyte differentiation.

The EMBO journal ·Vol. 17 ·No. 3 ·1998-02-02 ·Pages 774-85

Foley KP, McArthur GA, Quéva C, Hurlin PJ, Soriano P, Eisenman RN

Abstract

The switch from transcriptionally activating MYC-MAX to transcriptionally repressing MAD1-MAX protein heterodimers has been correlated with the initiation of terminal differentiation in many cell types. To investigate the function of MAD1-MAX dimers during differentiation, we disrupted the Mad1 gene by homologous recombination in mice. Analysis of hematopoietic differentiation in homozygous mutant animals revealed that cell cycle exit of granulocytic precursors was inhibited following the colony-forming cell stage, resulting in increased proliferation and delayed terminal differentiation of low proliferative potential cluster-forming cells. Surprisingly, the numbers of terminally differentiated bone marrow and peripheral blood granulocytes were essentially unchanged in Mad1 null mice. This imbalance between the frequencies of precursor and mature granulocytes was correlated with a compensatory decrease in granulocytic cluster-forming cell survival under apoptosis-inducing conditions. In addition, recovery of the peripheral granulocyte compartment following bone marrow ablation was significantly enhanced in Mad1 knockout mice. Two Mad1-related genes, Mxi1 and Mad3, were found to be expressed ectopically in adult spleen, indicating that functional redundancy and cross-regulation between MAD family members may allow for apparently normal differentiation in the absence of MAD1. These findings demonstrate that MAD1 regulates cell cycle withdrawal during a late stage of granulocyte differentiation, and suggest that the relative levels of MYC versus MAD1 mediate a balance between cell proliferation and terminal differentiation.

MeSH Terms
Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Bone Marrow/surgery Bone Marrow Cells/drug effects Cell Cycle/drug effects,physiology Cell Differentiation/drug effects,physiology Cells, Cultured Cytokines/pharmacology DNA-Binding Proteins/genetics,pharmacology Fluorouracil/pharmacology Genes/genetics Granulocytes/cytology,physiology Humans Macrophages/cytology,physiology Mice Mice, Inbred Strains Mice, Knockout Monocytes/cytology,physiology Multigene Family/genetics Mutagenesis, Site-Directed/genetics,physiology Proto-Oncogene Proteins c-myc/antagonists & inhibitors Repressor Proteins Sensitivity and Specificity
Chemicals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Cytokines DNA-Binding Proteins MXD1 protein, human Mad protein, mouse Proto-Oncogene Proteins c-myc Repressor Proteins Fluorouracil
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Foley K P
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North-Mailstop A2-025, P.O. Box 19024, Seattle, WA 98109-1024, USA.
McArthur G A
Quéva C
Hurlin P J
Soriano P
Eisenman R N
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/17.3.774
Published
1998-02-02
Pages
774-85
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1170426
Subset
IM
Grants
NICHD NIH HHS · HD 25326 · United States
NHLBI NIH HHS · HL54881 · United States
NCI NIH HHS · R01CA57138 · United States
External Links
PubMed source DOI: 10.1093/emboj/17.3.774 PMC Full Text View journal details
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