title: The Roles of p21(Waf1/CIP1) and Hus1 in Generation and Transmission of Damage Signals Stimulated by Low-Dose Alpha-Particle Irradiation.
abstract: Previously reported studies have demonstrated the involvement of p21(Waf1/CIP1) in radiation-induced bystander effects (RIBE). Mouse embryonic fibroblasts (MEFs) lacking Hus1 fail to proliferate in vitro, but inactivation of p21 allows for the continued growth of Hus1-deficient cells, indicating the close connection between p21 and Hus1 cells. In this study, wild-type MEFs, Hus1(+/+)p21(-/-) MEFs and p21(-/-)Hus1(-/-) MEFs were used in a series of radiation-induced bystander effect experiments, the roles of p21 and Hus1 in the induction and transmission of radiation-induced damage signals were investigated. Our results showed that after 5 cGy α particle irradiation, wild-type MEFs induced significant increases in γ-H2AX foci and micronuclei formation in bystander cells, whereas the bystander effects were not detectable in p21(-/-)Hus1(+/+) MEFs and were restored again in p21(-/-)Hus1(-/-) MEFs. Media transfer experiments showed that p21(-/-)Hus1(+/+) MEFs were deficient in the production bystander signals, but could respond to bystander signals. We further investigated the mitogen-activated protein kinases (MAPKs) that might be involved in the bystander effects. It was found that although knocking out p21 did not affect the expression of connexin43 and its phosphorylation, it did result in inactivation of some MAPK signal pathway kinases, including JNK1/2, ERK1/2 and p38, as well as a decrease in reactive oxygen species (ROS) levels in irradiated cells. However, the activation of MAPK kinases and the ROS levels in irradiated cells were restored in the cell line by knocking out Hus1. These results suggest that p21(Waf1/CIP1) and Hus1 play crucial roles in the generation and transmission of bystander damage signals after low-dose α-particle irradiation.
authors.affiliation: a  Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P.R. China;
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: b  National Laboratory of Biomacromolecules and Center for Computational and Systems Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ma
authors.affiliation: a  Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P.R. China;|c  Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei, Anhui 230031, P.R. China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: a  Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P.R. China;|c  Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei, Anhui 230031, P.R. China; and.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Chen
authors.affiliation: a  Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P.R. China;|c  Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei, Anhui 230031, P.R. China; and.
authors.forename: Hang
authors.initials: H
authors.lastname: Yuan
authors.affiliation: a  Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P.R. China;|c  Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei, Anhui 230031, P.R. China; and.
authors.forename: An
authors.initials: A
authors.lastname: Xu
authors.affiliation: b  National Laboratory of Biomacromolecules and Center for Computational and Systems Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China;
authors.forename: Haiying
authors.initials: H
authors.lastname: Hang
authors.affiliation: a  Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P.R. China;|c  Key Laboratory of Environmental Toxicology and Pollution Control Technology of Anhui Province, Hefei, Anhui 230031, P.R. China; and.|d  School of Nuclear Science and Technology, University of Science and Technology of China, Hefei, Anhui 230026, P.R. China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wu
mesh_terms: D065638:Absorption, Radiation; D000512:Alpha Particles; D000818:Animals; D024201:Bystander Effect / Q000502:physiology* / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000502:physiology / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D011829:Radiation Dosage
chemical_list: C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C509939:Hus1 protein, mouse