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p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis

p16(Ink4a) and p21(Cip1/Waf1) act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16(Ink4) and p21(Cip1/Waf1), namely, tumour promotion through chemotaxis...

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Autores principales: Okuma, Atsushi, Hanyu, Aki, Watanabe, Sugiko, Hara, Eiji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727112/
https://www.ncbi.nlm.nih.gov/pubmed/29234059
http://dx.doi.org/10.1038/s41467-017-02281-x
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author Okuma, Atsushi
Hanyu, Aki
Watanabe, Sugiko
Hara, Eiji
author_facet Okuma, Atsushi
Hanyu, Aki
Watanabe, Sugiko
Hara, Eiji
author_sort Okuma, Atsushi
collection PubMed
description p16(Ink4a) and p21(Cip1/Waf1) act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16(Ink4) and p21(Cip1/Waf1), namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16(Ink4) and p21(Cip1/Waf1) are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16 (Ink4) and p21 (Cip1/Waf1) reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function of p16 (Ink4a) and p21 (Waf1/Cip1) and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.
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spelling pubmed-57271122017-12-14 p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis Okuma, Atsushi Hanyu, Aki Watanabe, Sugiko Hara, Eiji Nat Commun Article p16(Ink4a) and p21(Cip1/Waf1) act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16(Ink4) and p21(Cip1/Waf1), namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16(Ink4) and p21(Cip1/Waf1) are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16 (Ink4) and p21 (Cip1/Waf1) reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function of p16 (Ink4a) and p21 (Waf1/Cip1) and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development. Nature Publishing Group UK 2017-12-12 /pmc/articles/PMC5727112/ /pubmed/29234059 http://dx.doi.org/10.1038/s41467-017-02281-x Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Okuma, Atsushi
Hanyu, Aki
Watanabe, Sugiko
Hara, Eiji
p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
title p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
title_full p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
title_fullStr p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
title_full_unstemmed p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
title_short p16(Ink4a) and p21(Cip1/Waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
title_sort p16(ink4a) and p21(cip1/waf1) promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727112/
https://www.ncbi.nlm.nih.gov/pubmed/29234059
http://dx.doi.org/10.1038/s41467-017-02281-x
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