期刊
NATURE IMMUNOLOGY
卷 17, 期 11, 页码 1312-1321出版社
NATURE PORTFOLIO
DOI: 10.1038/ni.3559
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资金
- Core Center of Excellence NIDDK grant [DK56465]
- US National Institutes of Health [1R01CA169784, 1R01CA133379, 1R01CA105129, 1R01CA149655, 5R01CA173636]
- William Lawrence and Blanche Hughes Foundation
- Leukemia & Lymphoma Society [6340-11, 6373-13]
- Chemotherapy Foundation
- V Foundation for Cancer Research
- Alex's Lemonade Stand Foundation for Childhood Cancer
- St. Baldrick's Cancer Research Foundation
- Damon Runyon Cancer Research Foundation (Berger Foundation Fellowship) [DRG-2234-15]
- Deutsche Forschungsgemeinschaft (Emmy Noether Research Group) [WO 2108/1-1]
- American-Italian Cancer Foundation (Alessandro and Catherine di Montezemolo endowment fund)
Hematopoietic stem cells (HSCs) are dormant in the bone marrow and can be activated in response to diverse stresses to replenish all blood cell types. We identified the ubiquitin ligase Huwe1 as a crucial regulator of HSC function via its post translational control of the oncoprotein N-myc (encoded by Mycn). We found Huwe1 to be essential for HSC self-renewal, quiescence and lymphoid-fate specification in mice. Through the use of a fluorescent fusion allele (Mycn(M)), we observed that N-myc expression was restricted to the most immature, multipotent stem and progenitor populations. N-myc expression was upregulated in response to stress or following loss of Huwel, which led to increased proliferation and stem-cell exhaustion. Mycn depletion reversed most of these phenotypes in vivo, which suggested that the attenuation of N-myc by Huwe1 is essential for reestablishing homeostasis following stress.
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