Interferon regulatory factor-1 regulates reconstituted extracellular matrix (rECM)-mediated apoptosis in human mammary epithelial cells.
Interactions between extracellular matrix (ECM) and mammary epithelial cells are critical for mammary gland homeostasis and apoptotic signaling. Interferon regulatory factor-1 (IRF-1) is a transcriptional regulator that promotes apoptosis during mammary gland involution and p53-independent apoptosis. We have recently shown that rapid cell surface tamoxifen (Tam) signaling promotes apoptosis in normal human mammary epithelial cells that were acutely damaged by expression of human papillomavirus type-16 E6 protein (*HMEC-E6). Apoptosis was mediated by recruitment of CREB-binding protein (CBP) to the gamma-activating sequence (GAS) element of the IRF-1 promoter, induction of IRF-1 and caspase-1/-3 activation. Here, we show that growth factor-depleted, reconstituted ECM (rECM), similar to Tam, promotes apoptosis in *HMEC-E6 cells through induction of IRF-1. Apoptosis was temporally associated with recruitment of CBP to the GAS element of the IRF-1 promoter, induction of IRF-1 expression and caspase-1/-3 activation. Small interfering RNA-mediated suppression of IRF-1 protein expression in *HMEC-E6 cells blocked (1) induction of IRF-1, (2) caspase-1/-3 activation and (3) apoptosis. These observations demonstrate that IRF-1 promotes rECM-mediated apoptosis and provide evidence that both rECM and rapid Tam signaling transcriptionally activate IRF-1 through recruitment of CBP to the IRF-1 GAS promoter complex.
Bowie
M L
ML
Department of Medicine, Duke University, Durham, NC 27710, USA.
Troch
M M
MM
Delrow
J
J
Dietze
E C
EC
Bean
G R
GR
Ibarra
C
C
Pandiyan
G
G
Seewaldt
V L
VL
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D050882:CREB-Binding Protein / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020218:Response Elements; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D018931:Antineoplastic Agents, Hormonal; C468762:IFI6 protein, human; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D013629:Tamoxifen; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D020169:Caspases