title: Plakoglobin deficiency protects keratinocytes from apoptosis.
abstract: The armadillo family protein plakoglobin (Pg) is a well-characterized component of anchoring junctions, where it functions to mediate cell-cell adhesion and maintain epithelial tissue integrity. Although its closest homolog beta-catenin acts in the Wnt signaling pathway to dictate cell fate and promote proliferation and survival, the role of Pg in these processes is not well understood. Here, we investigate how Pg affects the survival of mouse keratinocytes by challenging both Pg-null cells and their heterozygote counterparts with apoptotic stimuli. Our results indicate that Pg deletion protects keratinocytes from apoptosis, with null cells exhibiting delayed mitochondrial cytochrome c release and activation of caspase-3. Pg-null keratinocytes also exhibit increased messenger RNA and protein levels of the anti-apoptotic molecule Bcl-X(L) compared to heterozygote controls. Importantly, reintroduction of Pg into the null cells shifts their phenotype towards that of the Pg+/- keratinocytes, providing further evidence that Pg plays a direct role in regulating cell survival. Taken together, our results suggest that in addition to its adhesive role in epithelia, Pg may also function in contrast to the pro-survival tendencies of beta-catenin, to potentiate death in cells damaged by apoptotic stimuli, perhaps limiting the potential for the propagation of mutations and cellular transformation.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Dusek
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Godsel
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Strohecker
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.forename: Robert
authors.initials: R
authors.lastname: Harmon
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
authors.forename: Reto
authors.initials: R
authors.lastname: Caldelari
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D051185:gamma Catenin / Q000172:deficiency / Q000502:physiology*
chemical_list: C494812:Bcl2l1 protein, mouse; D012333:RNA, Messenger; D051020:bcl-X Protein; D051185:gamma Catenin; D045304:Cytochromes c; D053148:Caspase 3