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