Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest

B-cell activation and proliferation can be induced by a variety of extracellular stimuli. The fate of an activated B cell following mitogen stimulation can be dictated by the strength or duration of the signal, the expression of downstream signaling components necessary to promote proliferation, and...

Full description

Bibliographic Details
Main Authors:	Nikitin, Pavel A., Price, Alexander M., McFadden, Karyn, Yan, Christopher M., Luftig, Micah A.
Format:	Online
Language:	English
Published:	Public Library of Science 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907503/

id	pubmed-3907503
recordtype	oai_dc
spelling	pubmed-39075032014-02-04 Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest Nikitin, Pavel A. Price, Alexander M. McFadden, Karyn Yan, Christopher M. Luftig, Micah A. Research Article B-cell activation and proliferation can be induced by a variety of extracellular stimuli. The fate of an activated B cell following mitogen stimulation can be dictated by the strength or duration of the signal, the expression of downstream signaling components necessary to promote proliferation, and the cell intrinsic sensors and regulators of the proliferative program. Previously we have identified the DNA damage response (DDR) signaling pathway as a cell intrinsic sensor that is activated upon latent infection of primary human B cells by Epstein-Barr virus (EBV). Here we have assessed the role of the DDR as a limiting factor in the proliferative response to non-viral B-cell mitogens. We report that TLR9 activation through CpG-rich oligonucleotides induced B-cell hyper-proliferation and an ATM/Chk2 downstream signaling pathway. However, B-cell activation through the CD40 pathway coupled with interleukin-4 (IL-4) promoted proliferation less robustly and only a modest DDR. These two mitogens, but not EBV, modestly induced intrinsic apoptosis that was independent from the DDR. However, all three mitogens triggered a DDR-dependent G1/S phase cell cycle arrest preventing B-cell proliferation. The extent of G1/S arrest, as evidenced by release through Chk2 inhibition, correlated with B-cell proliferation rates. These findings have implications for the regulation of extra-follicular B-cell activation as it may pertain to the development of auto-immune diseases or lymphoma. Public Library of Science 2014-01-30 /pmc/articles/PMC3907503/ /pubmed/24498068 http://dx.doi.org/10.1371/journal.pone.0087299 Text en © 2014 Nikitin et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Nikitin, Pavel A. Price, Alexander M. McFadden, Karyn Yan, Christopher M. Luftig, Micah A.
spellingShingle	Nikitin, Pavel A. Price, Alexander M. McFadden, Karyn Yan, Christopher M. Luftig, Micah A. Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest
author_facet	Nikitin, Pavel A. Price, Alexander M. McFadden, Karyn Yan, Christopher M. Luftig, Micah A.
author_sort	Nikitin, Pavel A.
title	Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest
title_short	Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest
title_full	Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest
title_fullStr	Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest
title_full_unstemmed	Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest
title_sort	mitogen-induced b-cell proliferation activates chk2-dependent g1/s cell cycle arrest
description	B-cell activation and proliferation can be induced by a variety of extracellular stimuli. The fate of an activated B cell following mitogen stimulation can be dictated by the strength or duration of the signal, the expression of downstream signaling components necessary to promote proliferation, and the cell intrinsic sensors and regulators of the proliferative program. Previously we have identified the DNA damage response (DDR) signaling pathway as a cell intrinsic sensor that is activated upon latent infection of primary human B cells by Epstein-Barr virus (EBV). Here we have assessed the role of the DDR as a limiting factor in the proliferative response to non-viral B-cell mitogens. We report that TLR9 activation through CpG-rich oligonucleotides induced B-cell hyper-proliferation and an ATM/Chk2 downstream signaling pathway. However, B-cell activation through the CD40 pathway coupled with interleukin-4 (IL-4) promoted proliferation less robustly and only a modest DDR. These two mitogens, but not EBV, modestly induced intrinsic apoptosis that was independent from the DDR. However, all three mitogens triggered a DDR-dependent G1/S phase cell cycle arrest preventing B-cell proliferation. The extent of G1/S arrest, as evidenced by release through Chk2 inhibition, correlated with B-cell proliferation rates. These findings have implications for the regulation of extra-follicular B-cell activation as it may pertain to the development of auto-immune diseases or lymphoma.
publisher	Public Library of Science
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907503/
_version_	1612053036394348544

Mitogen-Induced B-Cell Proliferation Activates Chk2-Dependent G1/S Cell Cycle Arrest

Similar Items