Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response

dc.contributor.authorCollier, Ann E.
dc.contributor.authorWek, Ronald C.
dc.contributor.authorSpandau, Dan F.
dc.contributor.departmentDepartment of Dermatology, IU School of Medicineen_US
dc.date.accessioned2016-08-09T17:39:48Z
dc.date.available2016-08-09T17:39:48Z
dc.date.issued2015-10
dc.description.abstractThis study delineates the mechanisms by which UVB regulates protein synthesis in human keratinocytes and the importance of translational control in cell survival. Translation initiation is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2-P) that causes decreased global protein synthesis coincident with enhanced translation of selected stress-related transcripts, such as activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of the integrated stress response (ISR) that has cytoprotective functions as well as apoptotic signals through the downstream transcriptional regulator C/EBP homologous protein (CHOP; GADD153/DDIT3). We determined that UVB irradiation is a potent inducer of eIF2-P in keratinocytes, leading to decreased levels of translation initiation. However, expression of ATF4 or CHOP was not induced by UVB as compared with traditional ISR activators. The rationale for this discordant response is that ATF4 mRNA is reduced by UVB, and despite its ability to be preferentially translated, there are diminished levels of available transcript. Forced expression of ATF4 and CHOP protein before UVB irradiation significantly enhanced apoptosis, suggesting that this portion of the ISR is deleterious in keratinocytes following UVB. Inhibition of eIF2-P and translational control reduced viability following UVB that was alleviated by cycloheximide (CHX), indicating that translation repression through eIF2-P is central to keratinocyte survival.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationCollier, A. E., Wek, R. C., & Spandau, D. F. (2015). Translational repression protects human keratinocytes from UVB-induced apoptosis through a discordant eIF2 kinase stress response. The Journal of Investigative Dermatology, 135(10), 2502–2511. http://doi.org/10.1038/jid.2015.177en_US
dc.identifier.issn1523-1747en_US
dc.identifier.urihttps://hdl.handle.net/1805/10625
dc.language.isoen_USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionof10.1038/jid.2015.177en_US
dc.relation.journalThe Journal of Investigative Dermatologyen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectActivating Transcription Factor 4en_US
dc.subjectmetabolismen_US
dc.subjectApoptosisen_US
dc.subjectradiation effectsen_US
dc.subjectKeratinocytesen_US
dc.subjectStress, Physiologicalen_US
dc.subjectphysiologyen_US
dc.subjectTranscription Factor CHOPen_US
dc.subjecteIF-2 Kinaseen_US
dc.titleTranslational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Responseen_US
dc.typeArticleen_US
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