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Articles in PresS, published online ahead of print May 22, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00114.2002
Submitted on March 22, 2002
Accepted on May 16, 2002
1 Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, Louisiana, USA
* To whom correspondence should be addressed. E-mail: seldahr{at}tulane.edu.
Transcriptional repression is a key mechanism for the spatial specification of gene expression and cell fate determination during development. During kidney development, proliferating cell nuclear antigen (PCNA) is expressed in a population of primitive nephrons and blastema cells located in the nephrogenic zone. PCNA expression is downregulated rapidly as renal epithelial cells enter terminal differentiation and acquire functional characteristics. We have recently reported that the transcription factor p53 stimulates the terminal differentiation of renal epithelial cells via transcriptional activation of renal function genes (Saifudeen Z et al. J Clin Invest, 109: 1021-1030, 2002). Since p53-induced growth arrest in cultured cells correlates with downregulation of PCNA gene expression, we examined the impact of p53 inactivation on PCNA expression in mice and evaluated the effect of p53 on PCNA transcription. Immunohistochemistry revealed that the transition from nephrogenesis to terminal epithelial cell differentiation correlates with accumulation of the transcription factor p53. Importantly, the spatially restricted pattern of PCNA expression is disrupted in kidneys of p53-deficient pups, in which there was a redistribution of PCNA expression into the differentiation zone (without a change in total kidney PCNA content) and distortion of the tubular architecture. Electrophoretic mobility shift assays revealed that the binding of kidney nuclear extracts to the p53 response elements in human and rat PCNA promoters is developmentally regulated. Transient transfection assays performed in p53-deficient HeLa cells revealed that exogenous p53 strongly represses transcription from human PCNA promoter-reporter constructs. Interestingly, deletion of the p53-binding site confers enhanced responsiveness to p53-mediated repression, suggesting that transcriptional repression of PCNA by p53 is achieved by a mechanism other than direct DNA binding. Based on these results, we propose the hypothesis that p53-mediated transcriptional repression plays a role in the spatial restriction of PCNA gene expression during normal renal development.
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