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Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3
R S Chapman1, P C Lourenco, E Tonner
1Cancer Research Campaign (CRC) Laboratories, Department of Pathology, University of Edinburgh, Medical School, Edinburgh EH8 9AG UK.
Abstract:
Mammary gland involution is characterized by extensive apoptosis of the epithelial cells. At the onset of involution, Stat3 is specifically activated. To address the function of this signaling molecule in mammary epithelial apoptosis, we have generated a conditional knockout of Stat3 using the Cre-lox recombination system. Following weaning, a decrease in apoptosis and a dramatic delay of involution occurred in Stat3 null mammary tissue. Involution is normally associated with a significant increase in IGFBP-5 levels. This was observed in control glands, but not in the absence of Stat3. IGFBP-5 has been suggested to induce apoptosis by sequestering IGF-1 to casein micelles, thereby inhibiting its survival function. Our findings suggest that IGFBP-5 is a direct or indirect target for Stat3 and its upregulation is essential to normal involution. No marked differences were seen in the regulation of Stat5, Bcl-x(L), or Bax in the absence of Stat3. Precocious activation of Stat1 and increases in levels of p53 and p21 occurred and may act as compensatory mechanisms for the eventual initiation of involution observed in Stat3 null mammary glands. This is the first demonstration of the importance of a Stat factor in signaling the initiation of physiological apoptosis in vivo.
Insights
Signal transducer and activator of transcription 3 (Stat3) is crucial for mammary gland involution. Blocking Stat3 delays apoptosis and involution, highlighting its role in regulating IGFBP-5 and programmed cell death.
Area of Science:
- Cell biology
- Molecular biology
- Endocrinology
Background:
- Mammary gland involution involves extensive epithelial cell apoptosis.
- Signal transducer and activator of transcription 3 (Stat3) is activated at the onset of involution.
Purpose of the Study:
- To investigate the function of Stat3 in mammary epithelial cell apoptosis during involution.
- To elucidate the role of Stat3 in the regulation of involution-associated genes.
Main Methods:
- Generated a conditional knockout of Stat3 using the Cre-lox recombination system in mice.
- Analyzed mammary gland tissue following weaning to assess apoptosis and involution markers.
- Quantified levels of key proteins including IGFBP-5, Stat5, Bcl-x(L), Bax, p53, and p21.
Main Results:
- Stat3 knockout delayed mammary gland involution and reduced epithelial cell apoptosis.
- Upregulation of Insulin-like growth factor-binding protein 5 (IGFBP-5) during involution was dependent on Stat3.
- Stat1, p53, and p21 showed precocious activation in Stat3 null glands, suggesting compensatory mechanisms.
Conclusions:
- Stat3 signaling is essential for initiating physiological apoptosis during mammary gland involution.
- IGFBP-5 is a key downstream target of Stat3, mediating apoptosis during involution.
- Stat3 plays a critical role in the timely and efficient regression of the mammary gland.