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Updated: Aug 15, 2026

Indirect Immunofluorescence on Frozen Sections of Mouse Mammary Gland
Published on: December 1, 2015
C/EBPdelta is a crucial regulator of pro-apoptotic gene expression during mammary gland involution
Muthusamy Thangaraju1, Martina Rudelius, Brian Bierie
1Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA.
Abstract:
The STAT3 transcription factor is an important initiator of mammary gland involution in the mouse. This work shows that the STAT3 target gene CCAAT/enhancer binding protein delta (C/EBPdelta) is a crucial mediator of pro-apoptotic gene expression events in mammary epithelial cells. In the absence of C/EBPdelta, involution is delayed, the pro-apoptotic genes encoding p53, BAK, IGFBP5 and SGP2/clusterin are not activated, while the anti-apoptotic genes coding for BFL1 and Cyclin D1 are not repressed. Consequently, p53 targets such as survivin, BRCA1, BRCA2 and BAX are not regulated appropriately and protease activation is delayed. Furthermore, expression of MMP3 and C/EBPdelta during the second phase of involution is perturbed in the absence of C/EBPdelta. In HC11 cells, C/EBPdelta alone is sufficient to induce IGFBP5 and SGP2. It also suppresses Cyclin D1 expression and cooperates with p53 to elicit apoptosis. This study places C/EBPdelta between STAT3 and several pro- and anti-apoptotic genes promoting the physiological cell death response in epithelial cells at the onset of mammary gland involution.
Insights
CCAAT/enhancer binding protein delta (C/EBPdelta) is essential for mammary gland involution. Its absence delays cell death, disrupts gene regulation, and impairs protease activation, highlighting its role in epithelial cell apoptosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- Mammary gland involution is a complex process involving programmed cell death.
- Signal transducer and activator of transcription 3 (STAT3) initiates involution.
- The role of STAT3 target genes in mediating apoptosis during involution requires further elucidation.
Purpose of the Study:
- To investigate the role of CCAAT/enhancer binding protein delta (C/EBPdelta) in mammary epithelial cell apoptosis during involution.
- To determine if C/EBPdelta acts as a mediator between STAT3 and pro-apoptotic gene expression.
- To analyze the impact of C/EBPdelta deficiency on key genes regulating cell death and involution.
Main Methods:
- Analysis of gene expression in mouse models and HC11 cells.
- Investigating the regulation of pro- and anti-apoptotic genes.
- Assessing the impact on protease activation and involution timing.
Main Results:
- C/EBPdelta is a crucial mediator of pro-apoptotic gene expression (p53, BAK, IGFBP5, SGP2/clusterin) during involution.
- Absence of C/EBPdelta delays involution, prevents activation of pro-apoptotic genes, and fails to repress anti-apoptotic genes (BFL1, Cyclin D1).
- C/EBPdelta alone induces IGFBP5 and SGP2, suppresses Cyclin D1, and cooperates with p53 to promote apoptosis in HC11 cells.
Conclusions:
- C/EBPdelta acts as a key downstream mediator of STAT3 signaling during mammary gland involution.
- C/EBPdelta is essential for the timely activation of pro-apoptotic genes and repression of anti-apoptotic genes, facilitating physiological cell death.
- This study defines C/EBPdelta's critical position in the molecular cascade initiating mammary epithelial cell apoptosis during involution.
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