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Article: FBX4 mediates rapid cyclin D1 proteolysis upon DNA damage in immortalized esophageal epithelial cells

TitleFBX4 mediates rapid cyclin D1 proteolysis upon DNA damage in immortalized esophageal epithelial cells
Authors
KeywordsCyclin D1
F-box protein 4
ATM
DNA damage Response
Immortalized esophageal epithelial cells
Issue Date2021
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/wps/find/journaldescription.cws_home/622790/description
Citation
Biochemical and Biophysical Research Communications, 2021, v. 554, p. 76-82 How to Cite?
AbstractIt has been implied that deregulation of cyclin D1 turnover under stresses can facilitate genomic instability and trigger tumorigenesis. Much focus has been placed on identifying the E3 ligases responsible for mediating cyclin D1 degradation. However, the findings were quite controversial and cell type-dependent. Little is known about how cyclin D1 is regulated in precancerous cells upon DNA damage and which E3 ligases mediate the effects. Here we found cyclin D1 reduction is an early response to DNA damage in immortalized esophageal epithelial cells, with expression dropping to a low level within 1 h after γ-irradiation. Comparison of temporal expression of cyclin D1 upon DNA damage between immortalized NE083-hTERT and NE083-E6E7, the latter being p53/p21-defective, showed that DNA damage-induced rapid cyclin D1 reduction was p53-independent and occurred before p21 accumulation. Overexpression of cyclin D1 in NE083-E6E7 cells could attenuate G0/G1 cell cycle arrest at 1 h after irradiation. Furthermore, rapid reduction of cyclin D1 upon DNA damage was attributed to proteasomal degradation, as evidenced by data showing that proteasomal inhibition by MG132 blocked cyclin D1 reduction while cycloheximide facilitated it. Inhibition of ATM activation and knockdown of E3 ligase adaptor FBX4 reversed cyclin D1 turnover in immortalized NE083-hTERT cells. Further study showed that knockdown of FBX4 facilitated DNA breaks, as indicated by an increase in γ-H2AX foci in esophageal cancer cells. Taken together, the results substantiated a pivotal role of ATM and FBX4 in cyclin D1 proteolysis upon DNA damage in precancerous esophageal epithelial cells, implying that deregulation of the process may contribute to carcinogenesis of esophageal squamous cell carcinoma.
DescriptionHybrid open access
Persistent Identifierhttp://hdl.handle.net/10722/298683
ISSN
2023 Impact Factor: 2.5
2023 SCImago Journal Rankings: 0.770
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, J-
dc.contributor.authorYang, H-
dc.contributor.authorCheung, PY-
dc.contributor.authorTsao, SW-
dc.contributor.authorLv, L-
dc.contributor.authorCheung, ALM-
dc.date.accessioned2021-04-12T03:01:56Z-
dc.date.available2021-04-12T03:01:56Z-
dc.date.issued2021-
dc.identifier.citationBiochemical and Biophysical Research Communications, 2021, v. 554, p. 76-82-
dc.identifier.issn0006-291X-
dc.identifier.urihttp://hdl.handle.net/10722/298683-
dc.descriptionHybrid open access-
dc.description.abstractIt has been implied that deregulation of cyclin D1 turnover under stresses can facilitate genomic instability and trigger tumorigenesis. Much focus has been placed on identifying the E3 ligases responsible for mediating cyclin D1 degradation. However, the findings were quite controversial and cell type-dependent. Little is known about how cyclin D1 is regulated in precancerous cells upon DNA damage and which E3 ligases mediate the effects. Here we found cyclin D1 reduction is an early response to DNA damage in immortalized esophageal epithelial cells, with expression dropping to a low level within 1 h after γ-irradiation. Comparison of temporal expression of cyclin D1 upon DNA damage between immortalized NE083-hTERT and NE083-E6E7, the latter being p53/p21-defective, showed that DNA damage-induced rapid cyclin D1 reduction was p53-independent and occurred before p21 accumulation. Overexpression of cyclin D1 in NE083-E6E7 cells could attenuate G0/G1 cell cycle arrest at 1 h after irradiation. Furthermore, rapid reduction of cyclin D1 upon DNA damage was attributed to proteasomal degradation, as evidenced by data showing that proteasomal inhibition by MG132 blocked cyclin D1 reduction while cycloheximide facilitated it. Inhibition of ATM activation and knockdown of E3 ligase adaptor FBX4 reversed cyclin D1 turnover in immortalized NE083-hTERT cells. Further study showed that knockdown of FBX4 facilitated DNA breaks, as indicated by an increase in γ-H2AX foci in esophageal cancer cells. Taken together, the results substantiated a pivotal role of ATM and FBX4 in cyclin D1 proteolysis upon DNA damage in precancerous esophageal epithelial cells, implying that deregulation of the process may contribute to carcinogenesis of esophageal squamous cell carcinoma.-
dc.languageeng-
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/wps/find/journaldescription.cws_home/622790/description-
dc.relation.ispartofBiochemical and Biophysical Research Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCyclin D1-
dc.subjectF-box protein 4-
dc.subjectATM-
dc.subjectDNA damage Response-
dc.subjectImmortalized esophageal epithelial cells-
dc.titleFBX4 mediates rapid cyclin D1 proteolysis upon DNA damage in immortalized esophageal epithelial cells-
dc.typeArticle-
dc.identifier.emailTsao, SW: gswtsao@hku.hk-
dc.identifier.emailCheung, ALM: lmcheung@hku.hk-
dc.identifier.authorityTsao, SW=rp00399-
dc.identifier.authorityCheung, ALM=rp00332-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.bbrc.2021.03.089-
dc.identifier.pmid33784509-
dc.identifier.scopuseid_2-s2.0-85103429817-
dc.identifier.hkuros322144-
dc.identifier.volume554-
dc.identifier.spage76-
dc.identifier.epage82-
dc.identifier.isiWOS:000634962700012-
dc.publisher.placeUnited States-

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