IRF6 Promotes Cell Cycle Arrest and is Regulated by the Proteasome in a Cell Cycle-dependent Manner

Children's Memorial Research Center, the Robert H. Lurie Comprehensive Cancer Center, and the Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

^* To whom correspondence should be addressed. Email: zellis{at}childrensmemorial.org. mjchendrix{at}childrensmemorial.org.

	Abstract

Interferon Regulatory Factor 6 (IRF6) is a novel and unique member of the Interferon Regulatory Factor family of transcription factors. IRF6 has not been linked to the regulatory pathways or functions associated with other IRF family members, and the regulation and function of IRF6 remain unknown. We recently identified a protein interaction between IRF6 and the tumor suppressor maspin. To gain insight into the biological significance of the maspin-IRF6 interaction, we examined the regulation and function of IRF6 in relation to maspin in normal mammary epithelial cells. Our results demonstrate that in quiescent cells, IRF6 exists primarily in a non-phosphorylated state. However, cellular proliferation leads to rapid IRF6 phosphorylation, resulting in proteasome-dependent IRF6 degradation. These data are supported in situ by the increased expression of IRF6 in quiescent, differentiated lobulo-alveolar cells of the lactating mammary gland, when compared to proliferating ductal and glandular epithelial cells during pregnancy. Furthermore, re-expression of IRF6 in breast cancer cells results in cell cycle arrest, and the presence of maspin augments this response. These data support a model in which IRF6, in collaboration with maspin, promotes mammary epithelial cell differentiation by facilitating entry into the G(0) phase of the cell cycle.