Law F, Bonjour J P, Rizzoli R
Department of Medicine, Geneva University Hospital, Switzerland.
Endocrinology. 1994 May;134(5):2037-43. doi: 10.1210/endo.134.5.7512495.
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.
我们最近提供了证据，表明转化生长因子-β1（TGF-β）能够通过减少甲状旁腺激素相关蛋白（PTHrP）受体结合位点的数量，来调节负鼠肾（OK）细胞中PTHrP介导的反应。在本研究中，我们调查了TGF-β调节OK细胞中PTHrP受体密度的可能机制，这一领域在很大程度上仍未被探索。TGF-β处理能使PTHrP受体mRNA的稳态水平随时间依赖性降低，在6 - 10小时之间达到最低点（约降低3倍），先于18小时时对PTHrP受体结合的最大抑制。然后我们评估了18小时TGF-β暴露后导致的41%的结合减少是否可逆。24小时后，PTHrP结合活性有相当程度的恢复（与对照组相比降低23%），到48小时时几乎完全恢复。然而，在24小时的恢复期加入莫能菌素或环己酰亚胺，但不加入放线菌素（在该系统中能有效阻止TGF-β作用的剂量），可阻止PTHrP结合的恢复。去除TGF-β后，PTHrP受体信息在随后的24小时内显示出恢复的趋势。因此，TGF-β通过降低受体信息的表达，为OK上皮细胞中PTHrP受体的异源脱敏提供了一个例子。脱敏是可逆的，并且最初的24小时恢复期依赖于新受体蛋白的合成和加工。
