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The Cyclin D1 and Cyclin A Genes Are Targets of Activated PTH/PTHrP Receptors in Jansen’s Metaphyseal Chondrodysplasia

Canadian Institutes of Health Research Group in Skeletal Development and Remodeling (F.B.), Department of Physiology, University of Western Ontario, London, Ontario, Canada N6A 5C1; and Department of Biochemistry and Molecular Biology (P.L.), University of Calgary, Calgary, Alberta, Canada T2N 4N1

Address all correspondence and requests for reprints to: Frank Beier, Department of Physiology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada, N6A 5C1. E-mail: fbeier{at}uwo.ca.

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.

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