Targeted deletion of the S-phase-specific Myc antagonist Mad3 sensitizes neuronal and lymphoid cells to radiation-induced apoptosis

The Mad family comprises four basic-helix-loop-helix/leucine zipper protein s, Mad1, Mxi1, Mad3, and Mad4, which heterodimerize with Max and function a s transcriptional repressors. The balance between Myc-Max and Mad-Max compl exes has been postulated to influence cell proliferation and differentiatio n. 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 diff erentiation. The expression pattern of mad3 is unusual in that mad3 mRNA an d protein were found to be restricted to proliferating cells prior to diffe rentiation. We show here that during murine development mad3 is specificall y expressed in the S phase of the cell cycle in neuronal progenitor cells t hat are committed to differentiation. To investigate mad3 function, we disr upted 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 a nd neural progenitor cells was observed, implicating mad3 in the regulation of the cellular response to DNA damage.