The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia
The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia
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DOI：
10.1210/me.2001-0103
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发表时间：
2002-09-01
影响因子：
--
通讯作者：
Luvalle, P
中科院分区：
文献类型：
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作者：
Beier, F;Luvalle, P
詹森干骺端软骨发育不良（JMC）是一种常染色体显性遗传疾病，其特征是短肢侏儒症，骨化延迟和高钙血症。PTH/ PTHrP受体的激活突变已被确定为这种疾病的分子原因。虽然这些突变已被证明可以增加cAMP的积累，但对可能导致疾病发病机制的下游信号通路的可能靶基因知之甚少。在这里，我们证明，JMC突变的PTH/PTHrP受体诱导激活的细胞周期蛋白D1和细胞周期蛋白A启动子在原代小鼠软骨细胞和大鼠软骨肉瘤细胞。诱导细胞周期蛋白D1的表达是刺激E2 F依赖性转录突变受体所必需的。细胞周期蛋白D1和细胞周期蛋白A启动子的激活需要两个基因中的功能性cAMP反应元件。抑制蛋白激酶A或转录因子cAMP反应元件结合蛋白阻断突变受体对两种启动子的刺激，而抑制激活转录因子2、c-Fos或c-Jun仅具有微小的影响。总之，我们的数据表明，刺激细胞周期基因的表达和细胞周期的进展突变PTH/PTHrP受体有助于JMC的发病机制。
Jansen's metaphyseal chondrodysplasia (JMC) is an autosomal dominant disorder characterized by short-limbed dwarfism, delayed ossification, and hypercalcemia. Activating mutations in the PTH/ PTHrP receptor have been identified as the molecular cause of this disorder. Although these mutations have been shown to increase cAMP accumulation, little is known about possible target genes of the downstream signaling pathways that may contribute to the pathogenesis of the disease. Here we demonstrate that JMC mutations of the PTH/PTHrP receptor induce activation of the cyclin D1 and cyclin A promoters in primary mouse chondrocytes and rat chondrosarcoma cells. Induction of cyclin D1 expression is required for stimulation of E2F-dependent transcription by mutant receptors. Activation of the cyclin D1 and cyclin A promoters requires a functional cAMP response element in both genes. Inhibition of protein kinase A or the transcription factor cAMP response element binding protein blocks the stimulation of both promoters by mutant receptors, whereas inhibition of activating transcription factor 2, c-Fos, or c-Jun has only minor effects. In summary, our data suggest that stimulation of cell cycle gene expression and cell cycle progression by mutant PTH/PTHrP receptors contribute to the pathogenesis of JMC.