title: The role of calpains in ligand-induced degradation of the glucocorticoid receptor.
abstract: The glucocorticoid receptor (GR) is a ligand-activated transcription factor that mediates the effects of glucocorticoids in diverse cellular processes, including homeostasis, stress response, and inflammation. Glucocorticoids induce down-regulation of GR at both the mRNA and protein levels, causing reduced hormone responsiveness in response to long-term treatment with glucocorticoid. However, the mechanism involved in this process is still obscure. In this study, we examined whether calpain, a calcium-activated cysteine protease, is involved in ligand-stimulated degradation of GR. In COS-7 cells expressing the human GR, treatment with a calpain inhibitor abolished glucocorticoid-induced down-regulation of GR in a dose dependent manner. The protein level of endogenous GR was also elevated by inhibition of the calpain activity in HeLa cells treated with glucocorticoid. Furthermore, glucocorticoid-induced transcriptional activation of GR was enhanced in cells treated with a calpain inhibitor. These results indicate that calpain is involved in ligand-dependent degradation of GR, thus causing reduced hormone responsiveness.
authors.affiliation: Department of Biomedical Laboratory Science, College of Health Science, Yonsei University, Wonju 222-701, South Korea.
authors.forename: Yoon Suk
authors.initials: YS
authors.lastname: Kim
authors.forename: Jeonghan
authors.initials: J
authors.lastname: Kim
authors.forename: Yoonseo
authors.initials: Y
authors.lastname: Kim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Jesang
authors.initials: J
authors.lastname: Ko
mesh_terms: D000818:Animals; D019556:COS Cells; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D015853:Cysteine Proteinase Inhibitors; D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid; D002154:Calpain