title: Global dissociation of HuR-mRNA complexes promotes cell survival after ionizing radiation.
abstract: Ionizing radiation (IR) triggers adaptive changes in gene expression. Here, we show that survival after IR strongly depends on the checkpoint kinase Chk2 acting upon its substrate HuR, an RNA-binding protein that stabilizes and/or modulates the translation of target mRNAs. Microarray analysis showed that in human HCT116 colorectal carcinoma cells (WT), IR-activated Chk2 triggered the dissociation of virtually all of HuR-bound mRNAs, since IR did not dissociate HuR target mRNAs in Chk2-null (CHK2-/-) HCT116 cells. Accordingly, several HuR-interacting mRNAs encoding apoptosis- and proliferation-related proteins (TJP1, Mdm2, TP53BP2, Bax, K-Ras) dissociated from HuR in WT cells, but remained bound and showed altered post-transcriptional regulation in CHK2-/- cells. Use of HuR mutants that were not phosphorylatable by Chk2 (HuR(3A)) and HuR mutants mimicking constitutive phosphorylation by Chk2 (HuR(3D)) revealed that dissociation of HuR target transcripts enhanced cell survival. We propose that the release of HuR-bound mRNAs via an IR-Chk2-HuR regulatory axis improves cell outcome following IR.
authors.affiliation: Laboratory of Molecular Biology and Immunology, Baltimore, MD, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Masuda
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.forename: Mihee M
authors.initials: MM
authors.lastname: Kim
authors.forename: Subramanya
authors.initials: S
authors.lastname: Srikantan
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tominaga
authors.forename: Roza
authors.initials: R
authors.lastname: Selimyan
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martindale
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
mesh_terms: D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D064447:Checkpoint Kinase 2; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004847:Epithelial Cells / Q000528:radiation effects*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing
chemical_list: D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases