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

Foley, K P and McArthur, G A and Quéva, C and Hurlin, P J and Soriano, P and Eisenman, R N (1998) Targeted disruption of the MYC antagonist MAD1 inhibits cell cycle exit during granulocyte differentiation. The EMBO journal, 17 (3). pp. 774-785. ISSN 0261-4189

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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.

Item Type: Article or Abstract
Additional Information: This article is freely available in PubMed Central and at the journal's website.
DOI: 10.1093/emboj/17.3.774
PubMed ID: 9451002
PMCID: PMC1170426
Grant Numbers: PF-4103, DRG 076, R01CA57138, HL54881, HD 25326, HD24875
Keywords or MeSH Headings: 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;
Subjects: Cellular and Organismal Processes > Cell Physiology > Cell proliferation
Molecules > Genes > Oncogenes
Molecules > Proteins > Cell cycle proteins
Cellular and Organismal Processes > Cell Physiology > Cell differentiation
Depositing User: Library Staff
Date Deposited: 25 Nov 2008 21:38
Last Modified: 07 May 2010 20:43

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