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The active component of ginseng, ginsenoside Rb1, improves erythropoiesis in models of Diamond–Blackfan anemia by targeting Nemo-like kinase

Wilkes, Mark C. ; Jung, Kevin ; Lee, Britney E. ; Saxena, Mallika ; Sathianathen, Ryan S. ; Mercado, Jacqueline D. ; Perez, Cristina ; Flygare, Johan LU ; Narla, Anupama and Glader, Bertil , et al. (2021) In Journal of Biological Chemistry 297(3).
Abstract

Nemo-like kinase (NLK) is a member of the mitogen-activated protein kinase family of kinases and shares a highly conserved kinase domain with other mitogen-activated protein kinase family members. The activation of NLK contributes to the pathogenesis of Diamond–Blackfan anemia (DBA), reducing c-myb expression and mechanistic target of rapamycin activity, and is therefore a potential therapeutic target. Unlike other anemias, the hematopoietic effects of DBA are largely restricted to the erythroid lineage. Mutations in ribosomal genes induce ribosomal insufficiency and reduced protein translation, dramatically impacting early erythropoiesis in the bone marrow of patients with DBA. We sought to identify compounds that suppress NLK and... (More)

Nemo-like kinase (NLK) is a member of the mitogen-activated protein kinase family of kinases and shares a highly conserved kinase domain with other mitogen-activated protein kinase family members. The activation of NLK contributes to the pathogenesis of Diamond–Blackfan anemia (DBA), reducing c-myb expression and mechanistic target of rapamycin activity, and is therefore a potential therapeutic target. Unlike other anemias, the hematopoietic effects of DBA are largely restricted to the erythroid lineage. Mutations in ribosomal genes induce ribosomal insufficiency and reduced protein translation, dramatically impacting early erythropoiesis in the bone marrow of patients with DBA. We sought to identify compounds that suppress NLK and increases erythropoiesis in ribosomal insufficiency. We report that the active component of ginseng, ginsenoside Rb1, suppresses NLK expression and improves erythropoiesis in in vitro models of DBA. Ginsenoside Rb1–mediated suppression of NLK occurs through the upregulation of miR-208, which binds to the 30-UTR of NLK mRNA and targets it for degradation. We also compare ginsenoside Rb1–mediated upregulation of miR-208 with metformin-mediated upregulation of miR-26. We conclude that targeting NLK expression through miRNA binding of the unique 30-UTR is a viable alternative to the challenges of developing small-molecule inhibitors to target the highly conserved kinase domain of this specific kinase.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
297
issue
3
article number
100988
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • scopus:85113275983
  • pmid:34298020
ISSN
0021-9258
DOI
10.1016/j.jbc.2021.100988
language
English
LU publication?
yes
id
64a95c2c-5094-4d87-9c0c-90b7dcaf5dca
date added to LUP
2021-09-07 13:34:57
date last changed
2024-06-15 15:50:14
@article{64a95c2c-5094-4d87-9c0c-90b7dcaf5dca,
  abstract     = {{<p>Nemo-like kinase (NLK) is a member of the mitogen-activated protein kinase family of kinases and shares a highly conserved kinase domain with other mitogen-activated protein kinase family members. The activation of NLK contributes to the pathogenesis of Diamond–Blackfan anemia (DBA), reducing c-myb expression and mechanistic target of rapamycin activity, and is therefore a potential therapeutic target. Unlike other anemias, the hematopoietic effects of DBA are largely restricted to the erythroid lineage. Mutations in ribosomal genes induce ribosomal insufficiency and reduced protein translation, dramatically impacting early erythropoiesis in the bone marrow of patients with DBA. We sought to identify compounds that suppress NLK and increases erythropoiesis in ribosomal insufficiency. We report that the active component of ginseng, ginsenoside Rb1, suppresses NLK expression and improves erythropoiesis in in vitro models of DBA. Ginsenoside Rb1–mediated suppression of NLK occurs through the upregulation of miR-208, which binds to the 3<sup>0</sup>-UTR of NLK mRNA and targets it for degradation. We also compare ginsenoside Rb1–mediated upregulation of miR-208 with metformin-mediated upregulation of miR-26. We conclude that targeting NLK expression through miRNA binding of the unique 3<sup>0</sup>-UTR is a viable alternative to the challenges of developing small-molecule inhibitors to target the highly conserved kinase domain of this specific kinase.</p>}},
  author       = {{Wilkes, Mark C. and Jung, Kevin and Lee, Britney E. and Saxena, Mallika and Sathianathen, Ryan S. and Mercado, Jacqueline D. and Perez, Cristina and Flygare, Johan and Narla, Anupama and Glader, Bertil and Sakamoto, Kathleen M.}},
  issn         = {{0021-9258}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{The active component of ginseng, ginsenoside Rb1, improves erythropoiesis in models of Diamond–Blackfan anemia by targeting Nemo-like kinase}},
  url          = {{http://dx.doi.org/10.1016/j.jbc.2021.100988}},
  doi          = {{10.1016/j.jbc.2021.100988}},
  volume       = {{297}},
  year         = {{2021}},
}