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Pim1 kinase regulates c-Kit gene translation
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 le...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200960/ https://www.ncbi.nlm.nih.gov/pubmed/28042518 http://dx.doi.org/10.1186/s40164-016-0060-3 |
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author | An, Ningfei Cen, Bo Cai, Houjian Song, Jin H. Kraft, Andrew Kang, Yubin |
author_facet | An, Ningfei Cen, Bo Cai, Houjian Song, Jin H. Kraft, Andrew Kang, Yubin |
author_sort | An, Ningfei |
collection | PubMed |
description | 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 (35)S 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. |
format | Online Article Text |
id | pubmed-5200960 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-52009602016-12-30 Pim1 kinase regulates c-Kit gene translation An, Ningfei Cen, Bo Cai, Houjian Song, Jin H. Kraft, Andrew Kang, Yubin Exp Hematol Oncol Short Report 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 (35)S 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. BioMed Central 2016-12-30 /pmc/articles/PMC5200960/ /pubmed/28042518 http://dx.doi.org/10.1186/s40164-016-0060-3 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Short Report An, Ningfei Cen, Bo Cai, Houjian Song, Jin H. Kraft, Andrew Kang, Yubin Pim1 kinase regulates c-Kit gene translation |
title | Pim1 kinase regulates c-Kit gene translation |
title_full | Pim1 kinase regulates c-Kit gene translation |
title_fullStr | Pim1 kinase regulates c-Kit gene translation |
title_full_unstemmed | Pim1 kinase regulates c-Kit gene translation |
title_short | Pim1 kinase regulates c-Kit gene translation |
title_sort | pim1 kinase regulates c-kit gene translation |
topic | Short Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200960/ https://www.ncbi.nlm.nih.gov/pubmed/28042518 http://dx.doi.org/10.1186/s40164-016-0060-3 |
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