Differential regulation of MDR1 transcription by the p53 family members: Role of the DNA binding domain Journal Article


Authors: Johnson, R. A.; Shepard, E. M.; Scotto, K. W.
Article Title: Differential regulation of MDR1 transcription by the p53 family members: Role of the DNA binding domain
Abstract: Although the p53 family members share a similar structure and function, it has become clear that they differ with respect to their role in development and tumor progression. Because of the high degree of homology in their DNA binding domains (DBDs), it is not surprising that both p63 and p73 activate the majority of p53 target genes. However, recent studies have revealed some differences in a subset of the target genes affected, and the mechanism underlying this diversity has only recently come under investigation. Our laboratory has demonstrated previously that p53 represses transcription of the P-glycoprotein-encoding MDR1 gene via direct DNA binding through a novel p53 DNA-binding site (the HT site). By transient transfection analyses, we now show that p63 and p73 activate rather than repress MDR1 transcription, and they do so through an upstream promoter element (the alternative p63/p73 element (APE)) independent of the HT site. This activation is dependent on an intact DNA binding domain, because mutations within the p63DBD or p73DBD are sufficient to prevent APE-mediated activation. However, neither p63 nor p73 directly interact with the APE, suggesting an indirect mechanism of activation through this site. Most interestingly, when the p53DBD is replaced by the p63DBD, p53 is converted from a repressor working through the HT site to an activator working through the APE. Taken together, these data indicate that, despite considerable homology, the DBD of the p53 family members have unique properties and can differentially regulate gene targeting and transcriptional output by both DNA binding-dependent and -independent mechanisms. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords: controlled study; gene mutation; human cell; promoter region; dna-binding proteins; proteins; animals; gene targeting; genes; cell line; genetic transcription; protein interaction; transcription, genetic; cell line, tumor; protein p53; nuclear proteins; gene expression regulation; dna; genetic transfection; tumors; tumor suppressor proteins; phosphoproteins; tumor suppressor protein p53; mutagenesis, site-directed; binding sites; protein p63; trans-activators; sequence homology; protein family; dna binding; protein isoforms; genes, tumor suppressor; p-glycoprotein; multigene family; cell strain hepg2; tumor progression; multidrug resistance protein 1; repressor gene; protein p73; chemical bonds; homology; activation analysis; promoter regions (genetics); dna binding domains (dbd); promoter elements
Journal Title: Journal of Biological Chemistry
Volume: 280
Issue: 14
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2005-04-08
Start Page: 13213
End Page: 13219
Language: English
DOI: 10.1074/jbc.M414646200
PUBMED: 15634666
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 17" - "Export Date: 24 October 2012" - "CODEN: JBCHA" - "Source: Scopus"
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  1. Kathleen Weihs Scotto
    56 Scotto