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A novel role for IRF-1 as a suppressor of apoptosis
R S Chapman1, E K Duff, P C Lourenco
1Cancer Research Campaign (CRC) Laboratories, Department of Pathology, University of Edinburgh, Medical School, Edinburgh, EH8 9AG, UK.
Abstract:
The tumour suppressor IRF-1 is a transcription factor involved in the induction of apoptosis in several in vitro systems. Post-lactational involution of the mammary gland is characterized by extensive apoptosis of the epithelial cells. We have previously shown that signal transducer and activator of transcription (Stat) 3 drives apoptosis and involution in the mouse mammary gland. Since one of the downstream targets of the Stat signalling pathway is IRF-1, we have used IRF-1 knockout mice to address the potential role of this transcription factor in involution. Surprisingly, in the absence of IRF-1 significantly higher numbers of apoptotic cells were found in involuting glands at 48 h compared to control glands. In addition, the alveolar structure in IRF-1 null mammary glands had collapsed whereas in control glands the alveoli remained intact and distended. However, by 72 h control and null glands were morphologically similar suggesting that IRF-1 suppresses apoptosis only during the early, reversible, stage of involution. This suggests a survival role for IRF-1 in mammary epithelia and demonstrates a novel role for IRF-1 in vivo--suppression of premature epithelial apoptosis during mammary gland involution.
Insights
Interferon regulatory factor-1 (IRF-1) surprisingly promotes mammary epithelial cell survival during involution. IRF-1 suppresses premature apoptosis, revealing a novel in vivo role in mammary gland involution.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- The tumor suppressor Interferon Regulatory Factor-1 (IRF-1) induces apoptosis in vitro.
- Mammary gland involution involves significant epithelial cell apoptosis.
- Signal transducer and activator of transcription 3 (Stat3) drives mammary gland apoptosis and involution.
Purpose of the Study:
- To investigate the role of IRF-1 in mammary gland involution using IRF-1 knockout mice.
- To determine if IRF-1 influences the rate of apoptosis during post-lactational involution.
Main Methods:
- Utilized IRF-1 knockout mouse models.
- Analyzed mammary gland tissue at 48 and 72 hours post-involution.
- Quantified apoptotic cell numbers and assessed alveolar structure morphology.
Main Results:
- IRF-1 knockout glands showed significantly higher apoptosis at 48 hours compared to controls.
- Alveolar structure collapsed in IRF-1 null glands by 48 hours.
- By 72 hours, control and null glands were morphologically similar, indicating early-stage suppression.
Conclusions:
- IRF-1 plays a novel in vivo role in suppressing premature epithelial apoptosis during mammary gland involution.
- IRF-1 appears to promote mammary epithelial cell survival during the early, reversible stages of involution.
- These findings suggest a context-dependent role for IRF-1, acting as a suppressor of apoptosis in this specific in vivo setting.