title: CLCA2 as a p53-inducible senescence mediator.
abstract: p53 is a tumor suppressor gene that is frequently mutated in multiple cancer tissues. Activated p53 protein regulates its downstream genes and subsequently inhibits malignant transformation by inducing cell cycle arrest, apoptosis, DNA repair, and senescence. However, genes involved in the p53-mediated senescence pathway are not yet fully elucidated. Through the screening of two genome-wide expression profile data sets, one for cells in which exogenous p53 was introduced and the other for senescent fibroblasts, we have identified chloride channel accessory 2 (CLCA2) as a p53-inducible senescence-associated gene. CLCA2 was remarkably induced by replicative senescence as well as oxidative stress in a p53-dependent manner. We also found that ectopically expressed CLCA2 induced cellular senescence, and the down-regulation of CLCA2 by small interfering RNA caused inhibition of oxidative stress-induced senescence. Interestingly, the reduced expression of CLCA2 was frequently observed in various kinds of cancers including prostate cancer, whereas its expression was not affected in precancerous prostatic intraepithelial neoplasia. Thus, our findings suggest a crucial role of p53/CLCA2-mediated senescence induction as a barrier for malignant transformation.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Chizu
authors.initials: C
authors.lastname: Tanikawa
authors.forename: Hidewaki
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C120066:CLCA2 protein, human; D018118:Chloride Channels; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53