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Submitted on June 15, 2001
Accepted on May 13, 2002
1 CIHR Group in Skeletal Development and Remodeling, Department of Physiology, University of Western Ontario, London, ON, Canada, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada; # current affiliation: Department of Orthopedics, University of Florida at Gainesville; email: luvalpa@ortho.ufl.edu
* To whom correspondence should be addressed. 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 (PTH)/PTH-related (PTHrP) receptor have been identified as the molecular cause of this disorder. While 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 (RCS) 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 CREB blocks the stimulation of both promoters by mutant receptors, whereas inhibition of ATF-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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