title: Occludin is required for apoptosis when claudin-claudin interactions are disrupted.
abstract: Disruption of tight junctions is often seen during pathogen infection, inflammation, and tumor progression. Mislocalization of the tight junction proteins occludin and claudin in mammary epithelial monolayers leads to apoptosis through the extrinsic pathway. To further investigate the mechanism of this response, a normal mammary epithelial cell line (EpH4) as well as primary mammary epithelial cells were treated with a claudin-disrupting mimic peptide, DFYNP (aspartic acid-phenylalanine-tyrosine-asparagine-proline). Using fluorescent indicators, we found that caspase-3 activation, resulting from treatment with DFYNP, was restricted to EpH4 and primary mammary epithelial cells with mislocalized claudin-4. Mislocalized claudin-4 and occludin were colocalized in non-junctional puncta, and both molecules were found in the death-inducing signaling complex (DISC) where they colocalized with Fas, fas-associated protein with death domain (FADD), active caspase-8 and caspase-3 at distinct apical domains. Importantly, caspase-3 activation was totally repressed in primary mammary epithelial cells from occludin null mice. Thus, the apoptotic response appears to be initiated by the movement of occludin to the DISC suggesting that this molecule has signaling properties that initiate cell death when its tight junction location is disrupted.
authors.affiliation: Department of Physiology and Biophysics, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA.
authors.forename: N
authors.initials: N
authors.lastname: Beeman
authors.forename: P G
authors.initials: PG
authors.lastname: Webb
authors.forename: H K
authors.initials: HK
authors.lastname: Baumgartner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D062506:Claudin-4; D057167:Claudins / Q000235:genetics* / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin; D009842:Oligopeptides / Q000494:pharmacology; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C568157:CLDN4 protein, human; D062506:Claudin-4; D057167:Claudins; C568158:Cldn4 protein, mouse; D053418:Death Domain Receptor Signaling Adaptor Proteins; C505534:Fadd protein, mouse; C491899:Fas protein, mouse; D053200:Fas-Associated Death Domain Protein; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D009842:Oligopeptides; D019014:fas Receptor; D053148:Caspase 3; D053181:Caspase 8