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Control of Pim2 kinase stability and expression in transformed human haematopoietic cells

The oncogenic Pim2 kinase is overexpressed in several haematological malignancies, such as multiple myeloma and acute myeloid leukaemia (AML), and constitutes a strong therapeutic target candidate. Like other Pim kinases, Pim2 is constitutively active and is believed to be essentially regulated thro...

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Autores principales: Adam, Kévin, Lambert, Mireille, Lestang, Elsa, Champenois, Gabriel, Dusanter-Fourt, Isabelle, Tamburini, Jérôme, Bouscary, Didier, Lacombe, Catherine, Zermati, Yael, Mayeux, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672348/
https://www.ncbi.nlm.nih.gov/pubmed/26500282
http://dx.doi.org/10.1042/BSR20150217
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author Adam, Kévin
Lambert, Mireille
Lestang, Elsa
Champenois, Gabriel
Dusanter-Fourt, Isabelle
Tamburini, Jérôme
Bouscary, Didier
Lacombe, Catherine
Zermati, Yael
Mayeux, Patrick
author_facet Adam, Kévin
Lambert, Mireille
Lestang, Elsa
Champenois, Gabriel
Dusanter-Fourt, Isabelle
Tamburini, Jérôme
Bouscary, Didier
Lacombe, Catherine
Zermati, Yael
Mayeux, Patrick
author_sort Adam, Kévin
collection PubMed
description The oncogenic Pim2 kinase is overexpressed in several haematological malignancies, such as multiple myeloma and acute myeloid leukaemia (AML), and constitutes a strong therapeutic target candidate. Like other Pim kinases, Pim2 is constitutively active and is believed to be essentially regulated through its accumulation. We show that in leukaemic cells, the three Pim2 isoforms have dramatically short half-lives although the longer isoform is significantly more stable than the shorter isoforms. All isoforms present a cytoplasmic localization and their degradation was neither modified by broad-spectrum kinase or phosphatase inhibitors such as staurosporine or okadaic acid nor by specific inhibition of several intracellular signalling pathways including Erk, Akt and mTORC1. Pim2 degradation was inhibited by proteasome inhibitors but Pim2 ubiquitination was not detected even by blocking both proteasome activity and protein de-ubiquitinases (DUBs). Moreover, Pyr41, an ubiquitin-activating enzyme (E1) inhibitor, did not stabilize Pim2, strongly suggesting that Pim2 was degraded by the proteasome without ubiquitination. In agreement, we observed that purified 20S proteasome particles could degrade Pim2 molecule in vitro. Pim2 mRNA accumulation in UT7 cells was controlled by erythropoietin (Epo) through STAT5 transcription factors. In contrast, the translation of Pim2 mRNA was not regulated by mTORC1. Overall, our results suggest that Pim2 is only controlled by its mRNA accumulation level. Catalytically active Pim2 accumulated in proteasome inhibitor-treated myeloma cells. We show that Pim2 inhibitors and proteasome inhibitors, such as bortezomib, have additive effects to inhibit the growth of myeloma cells, suggesting that Pim2 could be an interesting target for the treatment of multiple myeloma.
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spelling pubmed-46723482015-12-17 Control of Pim2 kinase stability and expression in transformed human haematopoietic cells Adam, Kévin Lambert, Mireille Lestang, Elsa Champenois, Gabriel Dusanter-Fourt, Isabelle Tamburini, Jérôme Bouscary, Didier Lacombe, Catherine Zermati, Yael Mayeux, Patrick Biosci Rep Original Papers The oncogenic Pim2 kinase is overexpressed in several haematological malignancies, such as multiple myeloma and acute myeloid leukaemia (AML), and constitutes a strong therapeutic target candidate. Like other Pim kinases, Pim2 is constitutively active and is believed to be essentially regulated through its accumulation. We show that in leukaemic cells, the three Pim2 isoforms have dramatically short half-lives although the longer isoform is significantly more stable than the shorter isoforms. All isoforms present a cytoplasmic localization and their degradation was neither modified by broad-spectrum kinase or phosphatase inhibitors such as staurosporine or okadaic acid nor by specific inhibition of several intracellular signalling pathways including Erk, Akt and mTORC1. Pim2 degradation was inhibited by proteasome inhibitors but Pim2 ubiquitination was not detected even by blocking both proteasome activity and protein de-ubiquitinases (DUBs). Moreover, Pyr41, an ubiquitin-activating enzyme (E1) inhibitor, did not stabilize Pim2, strongly suggesting that Pim2 was degraded by the proteasome without ubiquitination. In agreement, we observed that purified 20S proteasome particles could degrade Pim2 molecule in vitro. Pim2 mRNA accumulation in UT7 cells was controlled by erythropoietin (Epo) through STAT5 transcription factors. In contrast, the translation of Pim2 mRNA was not regulated by mTORC1. Overall, our results suggest that Pim2 is only controlled by its mRNA accumulation level. Catalytically active Pim2 accumulated in proteasome inhibitor-treated myeloma cells. We show that Pim2 inhibitors and proteasome inhibitors, such as bortezomib, have additive effects to inhibit the growth of myeloma cells, suggesting that Pim2 could be an interesting target for the treatment of multiple myeloma. Portland Press Ltd. 2015-12-08 /pmc/articles/PMC4672348/ /pubmed/26500282 http://dx.doi.org/10.1042/BSR20150217 Text en © 2015 Authors http://creativecommons.org/licenses/by/3.0/ This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution Licence 3.0 (http://creativecommons.org/licenses/by/3.0/) .
spellingShingle Original Papers
Adam, Kévin
Lambert, Mireille
Lestang, Elsa
Champenois, Gabriel
Dusanter-Fourt, Isabelle
Tamburini, Jérôme
Bouscary, Didier
Lacombe, Catherine
Zermati, Yael
Mayeux, Patrick
Control of Pim2 kinase stability and expression in transformed human haematopoietic cells
title Control of Pim2 kinase stability and expression in transformed human haematopoietic cells
title_full Control of Pim2 kinase stability and expression in transformed human haematopoietic cells
title_fullStr Control of Pim2 kinase stability and expression in transformed human haematopoietic cells
title_full_unstemmed Control of Pim2 kinase stability and expression in transformed human haematopoietic cells
title_short Control of Pim2 kinase stability and expression in transformed human haematopoietic cells
title_sort control of pim2 kinase stability and expression in transformed human haematopoietic cells
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672348/
https://www.ncbi.nlm.nih.gov/pubmed/26500282
http://dx.doi.org/10.1042/BSR20150217
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