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Molecular and Cellular Biology, February 2001, p. 703-712, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.703-712.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Targeted Deletion of the S-Phase-Specific Myc Antagonist Mad3 Sensitizes Neuronal and Lymphoid Cells to Radiation-Induced Apoptosis

Christophe Quéva,dagger Grant A. McArthur,Dagger Brian M. Iritani, and Robert N. Eisenman*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024

Received 6 July 2000/Returned for modification 21 August 2000/Accepted 31 October 2000

The Mad family comprises four basic-helix-loop-helix/leucine zipper proteins, Mad1, Mxi1, Mad3, and Mad4, which heterodimerize with Max and function as transcriptional repressors. The balance between Myc-Max and Mad-Max complexes has been postulated to influence cell proliferation and differentiation. The expression patterns of Mad family genes are complex, but in general, the induction of most family members is linked to cell cycle exit and differentiation. The expression pattern of mad3 is unusual in that mad3 mRNA and protein were found to be restricted to proliferating cells prior to differentiation. We show here that during murine development mad3 is specifically expressed in the S phase of the cell cycle in neuronal progenitor cells that are committed to differentiation. To investigate mad3 function, we disrupted the mad3 gene by homologous recombination in mice. No defect in cell cycle exit and differentiation could be detected in mad3 homozygous mutant mice. However, upon gamma irradiation, increased cell death of thymocytes and neural progenitor cells was observed, implicating mad3 in the regulation of the cellular response to DNA damage.

* Corresponding author. Mailing address: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North---Mailstop A2-025, P.O. Box 19024, Seattle, WA 98109-1024. Phone: (206) 667-4445. Fax: (206) 667-6522. E-mail: eisenman{at}fred.fhcrc.org.

dagger Present address: AstraZeneca Transgenic Center, S-431 83 Mölndal, Sweden.

Dagger Present address: Peter MacCallum Cancer Institute, Division of Haematology and Medical Oncology, Victoria 8006, Australia.

Molecular and Cellular Biology, February 2001, p. 703-712, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.703-712.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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