Transforming growth factor-beta: a down-regulator of the parathyroid hormone-related protein receptor in renal epithelial cells.
We have recently provided evidence for the ability of transforming growth factor-beta 1 (TGF beta) to modulate PTH-related protein (PTHrP)-mediated responses in opossum kidney (OK) cells through reducing the number of PTHrP receptor-binding sites. In the present studies, we investigated the possible mechanisms by which TGF beta might regulate PTHrP receptor density in OK cells, an area that has remained largely unexplored. The steady state level of PTHrP receptor mRNA was time dependently reduced by TGF beta treatment, with the nadir (approximately 3-fold decrease) between 6-10 h, preceding the maximal inhibition on PTHrP receptor binding at 18 h. We then assessed whether the 41% reduction in binding consequent to 18-h TGF beta exposure was reversible. PTHrP-binding activity recovered considerably after 24 h (23% decrease compared with controls) and almost completely by 48 h. However, the addition of monensin or cycloheximide, but not actinomycin (at a dose effective in preventing TGF beta action in this system) during the 24-h recovery period prevented restoration of PTHrP binding. Upon removal of TGF beta, the PTHrP receptor message showed a trend toward recovery in the ensuing 24 h. Therefore, TGF beta provides an example of heterologous desensitization of the PTHrP receptor in OK epithelial cells by decreasing the expression of the receptor message. The desensitization was reversible, and the first 24-h recovery phase was dependent on synthesis and processing of new receptor proteins.
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Department of Medicine, Geneva University Hospital, Switzerland.
Bonjour
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JP
Rizzoli
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D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008985:Monensin / Q000494:pharmacology; D009893:Opossums; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D016212:Transforming Growth Factor beta; D003609:Dactinomycin; D008985:Monensin; D003513:Cycloheximide