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CEBPD suppresses prolactin expression and prolactinoma cell proliferation.
Yunguang Tong1, Jin Zhou, Jun Mizutani
1Academic Affairs, Los Angeles, California 90048, USA.
Molecular Endocrinology (Baltimore, Md.)
|October 8, 2011
Summary
CCAAT-enhancer-binding protein δ (CEBPD) regulates prolactin (PRL) levels and lactotroph cell growth. Lower CEBPD levels increase PRL, while its forced expression inhibits PRL production and cell proliferation, offering new therapeutic targets.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Biology
Background:
- Hyperprolactinemia, often caused by pituitary tumors, results in elevated prolactin (PRL) levels, leading to symptoms like galactorrhea and infertility.
- Increased PRL can stem from enhanced PRL gene expression or increased proliferation of PRL-secreting cells (lactotrophs).
- The relationship between PRL expression and lactotroph proliferation remains incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms linking PRL expression and lactotroph cell proliferation.
- To identify key regulatory factors involved in controlling both PRL production and cell growth.
Main Methods:
- Microarray-based gene expression profiling to identify regulatory genes.
- Utilizing PRL-secreting cell lines (GH3 and MMQ) for experimental manipulation.
- Employing small interfering RNA (siRNA) for gene knockdown and assessing effects on PRL expression and proliferation.
- Analyzing the binding of transcription factors to the PRL promoter and measuring promoter activity.
- Investigating interactions between transcription factors and their impact on gene regulation.
Main Results:
- CCAAT-enhancer-binding protein δ (CEBPD) was identified as a critical regulator of both PRL expression and lactotroph proliferation.
- CEBPD expression was significantly decreased (approx. 7-fold) in experimental rat prolactinoma cells.
- Forced expression of CEBPD inhibited PRL expression and proliferation in GH3 and MMQ cells.
- CEBPD knockdown using siRNA increased PRL expression in these cell lines.
- CEBPD directly binds to the PRL promoter, suppressing its activity by 96%.
- CEBPD interacts with Pit1, attenuating each other's binding to the PRL promoter.
- CEBPD suppresses the expression of key proliferation-related genes, including c-Myc, survivin, and cyclins B1, B2, and D1.
Conclusions:
- PRL expression and lactotroph cell proliferation are significantly regulated by the transcription factor CEBPD.
- CEBPD acts as a tumor suppressor in the context of prolactinoma by inhibiting both PRL production and cell growth.
- Understanding the CEBPD-Pit1 interaction and CEBPD's role in regulating proliferation-associated genes provides insights into hyperprolactinemia pathogenesis.
- CEBPD represents a potential therapeutic target for managing hyperprolactinemia and related pituitary tumors.
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