Interferon regulatory factor 6 promotes cell cycle arrest and is regulated by the proteasome in a cell cycle-dependent manner.
Interferon regulatory factor 6 (IRF6) is a novel and unique member of the IRF 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 nonphosphorylated 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 lobuloalveolar cells of the lactating mammary gland compared to its expression in proliferating ductal and glandular epithelial cells during pregnancy. Furthermore, the reexpression 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.
Bailey
Caleb M
CM
Children's Memorial Research Center, 2300 Children's Plaza, Box 222, Chicago, IL 60614-3394, USA.
Abbott
Daniel E
DE
Margaryan
Naira V
NV
Khalkhali-Ellis
Zhila
Z
Hendrix
Mary J C
MJ
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011247:Pregnancy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000502:physiology*; D015843:Serpins / Q000502:physiology
C109803:IRF6 protein, human; C528250:IRF6 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D050835:Interferon Regulatory Factors; D011993:Recombinant Fusion Proteins; C085344:SERPIN-B5; D015843:Serpins; D046988:Proteasome Endopeptidase Complex