title: Pim1 kinase regulates c-Kit gene translation.
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.
  
  
  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-Kit35S 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.
authors.affiliation: Department of Pathology, University of Chicago, Chicago, USA.
authors.forename: Ningfei
authors.initials: N
authors.lastname: An
authors.affiliation: Hollings Cancer Center, Medical University of South Carolina, Charleston, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Cen
authors.affiliation: Department of Pharmaceutical & Biomedical Sciences, University of Georgia, Athens, USA.
authors.forename: Houjian
authors.initials: H
authors.lastname: Cai
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, Tucson, USA.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Song
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, Tucson, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kraft
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, DUMC 3961, Durham, NC 27710 USA.
authors.forename: Yubin
authors.identifier: 0000-0001-6678-8732
authors.initials: Y
authors.lastname: Kang
keywords: Hematopoiesis; Hematopoietic progenitor cells; Hematopoietic stem cells; PIM kinase; Receptor tyrosine kinase; Regulation; Serine/threonine kinase; Translation; c-Kit