title: Loss of cathepsin L activity promotes claudin-1 overexpression and intestinal neoplasia.
abstract: Intestinal epithelial integrity and polarity are maintained by cohesive interactions between cells via the formation of tight junctions. Irregularities in tight junctions have only recently been found to be associated with the initiation and progression of intestinal neoplasia. The claudin family of proteins is integral to the structure and function of the tight junction but little is known of the molecular events that regulate the expression of these components. The present report identifies cathepsin L, classically a lysosomal cysteine protease, as being induced during intestinal epithelial cell polarization and differentiation. Inhibition of intracellular cathepsin L activity results in the accumulation of disorganized cell layers and a decline in the expression of differentiation markers in cultured intestinal epithelial cells. This coincides with a rapid up-regulation of claudin-1 protein accumulation. Mutant mice defective in cathepsin L activity (furless) display an elevated level of intestinal claudin-1 and claudin-2 expression. Loss of cathepsin L activity leads to a marked increase in tumor multiplicity in the intestine of Apc(Min) mice. Given the traditionally viewed biological role of cathepsin L in the processing of lysosomal content as well as in pathological extracellular matrix remodeling, the results here demonstrate an as yet unsuspected intracellular role for this protease in normal intestinal epithelial polarization and initiation of neoplasia.
authors.affiliation: Département d'Anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, 3001 12e ave Nord, Fleurimont, QC, Canada, J1H 5N4. francois.boudreau@usherbrooke.ca
authors.forename: François
authors.initials: F
authors.lastname: Boudreau
authors.forename: Carine R
authors.initials: CR
authors.lastname: Lussier
authors.forename: Sébastien
authors.initials: S
authors.lastname: Mongrain
authors.forename: Mathieu
authors.initials: M
authors.lastname: Darsigny
authors.forename: Julie L
authors.initials: JL
authors.lastname: Drouin
authors.forename: Geneviève
authors.initials: G
authors.lastname: Doyon
authors.forename: Eun Ran
authors.initials: ER
authors.lastname: Suh
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Beaulieu
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rivard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Perreault
mesh_terms: D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D062445:Claudin-1; D003546:Cysteine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits; D015854:Up-Regulation / Q000502:physiology
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008565:Membrane Proteins; D011480:Protease Inhibitors; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse