Rb family proteins enforce the homeostasis of quiescent hematopoietic stem cells by repressing Socs3 expression
Open accessAbstract
Prolonged exit from quiescence by hematopoietic stem cells (HSCs) progressively impairs their homeostasis in the bone marrow through an unidentified mechanism. We show that Rb proteins, which are major enforcers of quiescence, maintain HSC homeostasis by positively regulating thrombopoietin (Tpo)-mediated Jak2 signaling. Rb family protein inactivation triggers the progressive E2f-mediated transactivation of Socs3, a potent inhibitor of Jak2 signaling, in cycling HSCs. Aberrant activation of Socs3 impairs Tpo signaling and leads to impaired HSC homeostasis. Therefore, Rb proteins act as a central hub of quiescence and homeostasis by coordinating the regulation of both cell cycle and Jak2 signaling in HSCs.
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NR4A1 and SOCS3 play a role in supporting HSC homeostasis by dampening inflammatory responses.
“Both NR4A1 and SOCS3 have been noted to play a role in supporting HSC homeostasis by dampening inflammatory responses (Freire and Conneely, 2018; Kim et al., 2017).”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Kim et al., 2017
The Results and discussion section, “Level of Socs3 expression dictates HSC homeostasis in the BM” (page unavailable), reports that Socs3 overexpression impairs HSC homeostasis—the opposite of the role attributed to SOCS3 here. The Concluding remarks instead link preserved homeostasis to repression of Socs3 and discuss Tpo/Jak2 signaling, not dampening inflammatory responses. This paper does not address NR4A1. (LLM, conf=0.90)
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- Authors
- Kim, E., Cheng, Y., Bolton-Gillespie, E., Cai, X., Ma, C., Tarangelo, A., Le, L., Jambhekar, M., Raman, P., Hayer, K. E., Wertheim, G., Speck, N. A., Tong, W., & Viatour, P.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of Pennsylvania (US)
- Corresponding author
- Viatour, Patrick
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2017-05-26
- Volume
- 214
- Issue
- 7
- Pages
- 1901-1912
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5502420
- OpenAlex
- W2618176120
- Cited by
- 18
- References
- 35
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- W.W. Smith Charitable Trust
- Foerderer Award
- Alex's Lemonade Stand Foundation
- Canuso Foundation
- American Cancer Society (RSG-16-233-01-TBE)
- Center for Childhood Cancer Research
- Children’s Hospital of Philadelphia
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- Rb family proteins, hematopoietic stem cells, HSC quiescence, HSC homeostasis, SOCS3, thrombopoietin, JAK2 signaling, E2F transcription factors, cell cycle regulation, bone marrow
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Cell Cycle, Cell Division, Hematopoietic Stem Cells, Homeostasis, Mice, Transgenic, Phosphorylation, Thrombopoietin, Immunoblotting, Transcriptional Activation, Retinoblastoma Protein, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, RNA Interference, Cell Proliferation, E2F Transcription Factors, Retinoblastoma-Like Protein p130, Retinoblastoma-Like Protein p107, Janus Kinase 2
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