cAMP-response element binding protein (CREB) regulates cyclosporine-A-mediated down-regulation of cathepsin B and L synthesis.
Cyclosporin A (CsA) is an immunosuppressant with severe side effects including gingival overgrowth. We have previously reported that CsA impairs the activity of the lysosomal enzymes cathepsin B and L in human gingival fibroblasts (HGFs). Here, we have examined the effects of CsA on the DNA-binding activity of the cyclic AMP response element-binding protein (CREB) and cell viability, and the effects of CREB on cathepsin B and L synthesis and activity in HGFs. We have confirmed that CsA down-regulates cathepsin B and L synthesis. Further, CsA has no effect on cell viability and dramatically impairs CREB-DNA binding activity. Importantly, the synthesis of cathepsin B and L is down-regulated, and their activity is also significantly impaired in HGFs transfected with plasmid expressing dominant-negative CREB. These results suggest that CREB is essential for the CsA-mediated down-regulation of cathepsin B and L synthesis in HGFs.
Omori
Kazuhiro
K
Department of Pathophysiology-Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Naruishi
Koji
K
Yamaguchi
Tomoko
T
Li
Shun-Ai
SA
Yamaguchi-Morimoto
Mayumi
M
Matsuura
Kaori
K
Arai
Hideo
H
Takei
Kohji
K
Takashiba
Shogo
S
D050882:CREB-Binding Protein / Q000502:physiology*; D002401:Cathepsin B / Q000096:biosynthesis* / Q000187:drug effects; D056668:Cathepsin L; D002403:Cathepsins / Q000096:biosynthesis* / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000187:drug effects; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005881:Gingiva / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D014162:Transfection; D052118:Lysosomal-Associated Membrane Protein 1
D050882:CREB-Binding Protein; D002401:Cathepsin B; D056668:Cathepsin L; D002403:Cathepsins; D016572:Cyclosporine; D003546:Cysteine Endopeptidases; D051907:Lysosomal Membrane Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C494363:CREBBP protein, human; C534281:CTSL protein, human