Autoregulation of pituitary corticotroph SOCS-3 expression: Characterization of the murine SOCS-3 promoter
Open accessAbstract
Pituitary corticotroph SOCS-3 is a novel intracellular regulator of leukemia inhibitory factor (LIF)-mediated proopiomelanocortin gene expression and adrenocorticotropic hormone (ACTH) secretion, inhibiting LIF-activated Janus kinase-signal transducers and activators of transcription (STAT) signaling in a negative autoregulatory loop. We now demonstrate in corticotroph AtT-20 cells that LIF-stimulated endogenous SOCS-3 mRNA expression is blocked in stable transfectants of SOCS-3 wild type or in dominant negative STAT-3 mutants, respectively. We characterized ≈3.8-kb genomic 5′ sequence of murine SOCS-3, including ≈2.9-kb sequence upstream of the transcription start site (+1), which was determined by 5′ rapid amplification of cDNA ends and RNase protection assay. Different 5′ constructs were cloned into the pGL3Basic vector, and luciferase activity was assayed in transiently transfected ACTH-secreting corticotroph AtT-20 cells. A STAT-1/STAT-3 binding element, located at nucleotides −72 to −64, was essential for LIF stimulation of SOCS-3 promoter activity. LIF induced 10-fold increased luciferase activity in a wild-type construct spanning −2757 to +929 bases. However, deletion or point mutation of the STAT-1/STAT-3 binding element abrogated LIF action (2- to 3-fold). Electrophoretic mobility-shift assay analysis confirmed specific binding of STAT-1 and STAT-3 to this region. These results characterize the genomic 5′ region of murine SOCS-3 and identify an important STAT-1/STAT-3 binding element therein. Thus, LIF-stimulated SOCS-3 gene expression is at least in part mediated by STAT-3 and STAT-1. The cytokine inhibitor SOCS-3 acts in a negative loop to autoregulate its own gene expression, thus limiting its accumulation in the corticotroph cell. These results demonstrate a mechanism for corticotroph plasticity with rapid “on” and “off” ACTH induction in response to neuro-immuno-endocrine stimuli, such as LIF.
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STAT3 activates transcription of Socs3 mRNA by associating with the 5' promoter region of the Socs3 gene.
“STAT3 activates the transcription of Socs3 mRNA by associating with the 5Ј promoter region of the Socs3 gene (17).”
From The Comparative Roles of Suppressor of Cytokine Signaling-1 and -3 in the Inhibition and Desensitization of Cytokine Signaling (2006) · cites this paper as [17]
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- Authors
- Auernhammer, C. J., Bousquet, C., & Melmed, S.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-06-08
- Volume
- 96
- Issue
- 12
- Pages
- 6964-6969
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC22025
- OpenAlex
- W2020438689
- Cited by
- 284
- References
- 0
- Citations by year
- 2024: 3 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 10 · 2015: 3 · 2014: 9 · 2013: 13 · 2012: 8
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk050238-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK50238)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- SOCS3, corticotrophs, pituitary gland, leukemia inhibitory factor, STAT1, STAT3, transcriptional autoregulation, ACTH secretion, proopiomelanocortin, negative feedback loop, AtT-20 cells
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Base Sequence, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Molecular Sequence Data, Pituitary Gland, Promoter Regions, Genetic, Proteins, Repressor Proteins, RNA, Messenger, Transcription Factors, Signal Transduction, Trans-Activators, src Homology Domains, STAT1 Transcription Factor, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice
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