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Loss of cathepsin L activity promotes claudin‐1 overexpression and intestinal neoplasia
Author(s) -
Boudreau Francois,
Lussier Carine R.,
Mongrain Sébastien,
Darsigny Mathieu,
Drouin Julie L.,
Doyon Geneviève,
Suh Eun Ran,
Beaulieu JeanFrancois,
Rivard Nathalie,
Perreault Nathalie
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-8113com
Subject(s) - tight junction , cathepsin , claudin , microbiology and biotechnology , intracellular , cathepsin l , cathepsin b , cell polarity , cysteine protease , biology , cathepsin e , barrier function , intestinal mucosa , chemistry , proteases , cell , cathepsin o , biochemistry , medicine , enzyme
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.— Boudreau, F., Lussier, C. R., Mongrain, S., Darsigny, M., Drouin, J. L., Doyon, G., Suh, E. R., Beaulieu, J.‐F., Rivard, N., Perreault, N. Loss of cathepsin L activity promotes claudin‐1 overexpression and intestinal neoplasia. FASEB J . 21, 3853–3865 (2007)