Signal transducer and activator of transcription 3 and the phosphatidylinositol 3‐kinase regulatory subunits p55α and p50α regulate autophagy in vivo
Open accessAbstract
Mammary gland involution involves a process that includes one of the most dramatic examples of cell death in an adult mammalian organism. We have previously shown that signal transducer and activator of transcription 3 (Stat3) regulates a lysosomal pathway of cell death in the first 48 h of involution and induces lysosome leakiness in mammary epithelial cells. Interestingly, Stat3 is associated also with the striking induction of autophagy that occurs concomitantly with cell death, presumably as a transient survival mechanism. The phosphatidylinositol 3‐kinase regulatory subunits p55α and p50α are dramatically and specifically upregulated at the transcriptional level by Stat3 at the onset of involution. We show here that ablation of either Stat3 or p55α/p50α in vivo affects autophagy during involution. We used two different cell culture models (normal mammary epithelial cells and mouse embryonic fibroblasts) to further investigate the role of p55α/p50α in autophagy regulation. Our results demonstrate a direct role for p55α/p50α as inhibitors of autophagy mediated by p85α. Thus, Stat3 and its downstream targets p55α/p50α are key regulators of the balance between autophagy and cell death in vivo.
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STAT3 promotes autophagy, e.g., LIF/STAT3 and OSM/STAT3 signaling promote autophagy in mammary gland cells by upregulating both p55 and p50 isoforms of PI3K regulatory subunit 1, PIK3R1.
“STAT3 also promotes autophagy, e.g., leukemia inhibitory factor/STAT3 and oncostatin M/STAT3 signaling promote autophagy in mammary gland cells by upregulating both the p55 and p50 isoforms of PI3K regulatory subunit 1, PIK3R1 (Pensa et al., 2014).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Pensa et al., 2014
The Results section reports that OSM activates Stat3, increases p55α and p50α expression in mammary epithelial cells, and appears to induce autophagy. It identifies LIF as an inducer of these isoforms in the mammary gland, but does not show that LIF promotes autophagy. The authors also say they could not isolate the isoforms’ direct contribution to the OSM response, so the claimed mechanism is stronger than their evidence. (LLM, conf=0.85)
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- Authors
- Pensa, S., Lloyd‐Lewis, B., Sargeant, T. J., Resemann, H. K., Kahn, C. R., & Watson, C. J.
- Affiliations
- University of Cambridge (GB)
- Joslin Diabetes Center (US)
- Corresponding author
- Watson, Christine J.
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2014-09-24
- Volume
- 281
- Issue
- 20
- Pages
- 4557-4567
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- PMC
- PMC4364409
- OpenAlex
- W2040488651
- Cited by
- 28
- References
- 29
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 8 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion)
- PubMed Central (acceptedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- BBSRC and MRC (BB/D012937/1, MR/J001023/1)
- Marie Curie IEF fellowship (273365)
- Cambridge Cancer Centre
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- STAT3, PI3K regulatory subunit, autophagy, mammary gland involution, lysosomal cell death, p85α, mammary epithelial cells, autophagy regulation, transcriptional regulation
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Embryo, Mammalian, Female, Fibroblasts, Immunoenzyme Techniques, Mammary Glands, Animal, Mice, Inbred C57BL, RNA, Messenger, Blotting, Western, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, Mice, Class Ia Phosphatidylinositol 3-Kinase, Real-Time Polymerase Chain Reaction
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