Mechanisms of p53-mediated repression of the human polycystic kidney disease-1 promoter.
We previously reported that the tumor suppressor protein p53 participates in a negative feedback loop to fine-tune PKD1 gene expression. This physiological pathway is believed to prevent polycystin-1 overexpression and thus renal cysts. The present study examined the mechanisms of p53-mediated repression of PKD1. The 5'-upstream region of the human PKD1 gene is TATA-less, GC-rich, and contains four consensus p53 binding sites at positions -2.7 kb (BS4), -1.2 kb (BS3), -0.8 kb (BS2), and -0.2 kb (BS1), respectively. PKD1BS1-4 are bound to endogenous p53 in vivo and in vitro. Transient transfection assays in inner medullary collecting duct cells revealed that disruption of PKD1BS1 enhances baseline PKD1 promoter activity; in contrast, disruption of PKD1BS4 suppressed PKD1 transcription. PKD1BS1 confers p53-mediated repression when substituted for the p53 enhancer element in the bradykinin B2 receptor gene, indicating that PKD1BS1 is a bona fide p53 repressor element. Moreover, PKD1BS1 requires intact BS2-4 and cellular histone deacetylase activity for full functional activity. Indeed, the PKD1BS1/4 regions are occupied by a complex containing HDAC1/2 and mSin3. These findings suggest a model whereby p53 exerts a biphasic control on PKD1 gene transcription, depending on cellular context and the cognate cis-acting element.
van Bodegom
Diederik
D
Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Roessingh
Wijnand
W
Pridjian
Andrew
A
El Dahr
Samir S
SS
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050396:TRPP Cation Channels / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D050396:TRPP Cation Channels; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human
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