Pim1 kinase regulates c-Kit gene translation.
Journal Article (Journal Article)
BACKGROUND: Receptor tyrosine kinase, c-Kit (CD117) plays a pivotal role in the maintenance and expansion of hematopoietic stem/progenitor cells (HSPCs). Additionally, over-expression and/or mutational activation of c-Kit have been implicated in numerous malignant diseases including acute myeloid leukemia. However, the translational regulation of c-Kit expression remains largely unknown. METHODS AND RESULTS: We demonstrated that loss of Pim1 led to specific down-regulation of c-Kit expression in HSPCs of Pim1-/- mice and Pim1-/-2-/-3-/- triple knockout (TKO) mice, and resulted in attenuated ERK and STAT3 signaling in response to stimulation with stem cell factor. Transduction of c-Kit restored the defects in colony forming capacity seen in HSPCs from Pim1-/- and TKO mice. Pharmacologic inhibition and genetic modification studies using human megakaryoblastic leukemia cells confirmed the regulation of c-Kit expression by Pim1 kinase: i.e., Pim1-specific shRNA knockdown down-regulated the expression of c-Kit whereas overexpression of Pim1 up-regulated the expression of c-Kit. Mechanistically, inhibition or knockout of Pim1 kinase did not affect the transcription of c-Kit gene. Pim1 kinase enhanced c-Kit 35S methionine labeling and increased the incorporation of c-Kit mRNAs into the polysomes and monosomes, demonstrating that Pim1 kinase regulates c-Kit expression at the translational level. CONCLUSIONS: Our study provides the first evidence that Pim1 regulates c-Kit gene translation and has important implications in hematopoietic stem cell transplantation and cancer treatment.
Full Text
Duke Authors
Cited Authors
- An, N; Cen, B; Cai, H; Song, JH; Kraft, A; Kang, Y
Published Date
- 2016
Published In
Volume / Issue
- 5 /
Start / End Page
- 31 -
PubMed ID
- 28042518
Pubmed Central ID
- PMC5200960
International Standard Serial Number (ISSN)
- 2162-3619
Digital Object Identifier (DOI)
- 10.1186/s40164-016-0060-3
Language
- eng
Conference Location
- England