The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia.
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.
Canadian Institutes of Health Research Group in Skeletal Development and Remodeling, University of Western Ontario, London, Ontario, Canada N6A 5C1. fbeier@uwo.ca
Frank
F
Beier
Phyllis
P
LuValle
D000818:Animals; D018797:Cell Cycle Proteins; D019902:Chondrocytes; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019925:Cyclin A / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005097:Exostoses, Multiple Hereditary / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism; D018016:Receptors, Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D014157:Transcription Factors; D019938:Cyclin D1; D017868:Cyclic AMP-Dependent Protein Kinases