Pim1 kinase regulates c-Kit gene translation

Ningfei An, Bo Cen, Houjian Cai, Jin H. Song, Andrew Kraft, Yubin Kang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number31
JournalExperimental Hematology and Oncology
Volume5
Issue number1
DOIs
StatePublished - Dec 30 2016

Keywords

  • C-Kit
  • Hematopoiesis
  • Hematopoietic progenitor cells
  • Hematopoietic stem cells
  • PIM kinase
  • Receptor tyrosine kinase
  • Regulation
  • Serine/threonine kinase
  • Translation

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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