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Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53
D H Mack1, J Vartikar, J M Pipas
1Department of Molecular Genetics and Cell Biology, University of Chicago, Illinois 60637.
Abstract:
The p53 protein is apparently central to the development of human cancers because both alleles are often found to be mutated in different tumour types. In addition, wild-type p53 can inhibit transformation by viral and cellular oncogenes in vitro, so p53 has been classified as a tumour suppressor. Investigations of the normal function of p53 have indicated that at least one of its functions could involve the activation of gene expression through the binding of specific DNA-regulatory sequences. Also, overexpression of p53 can mediate growth arrest and repress transcription from a variety of promoters. We demonstrate here both in vivo and in vitro that expression of wild-type p53 specifically represses the activity of promoters whose initiation is dependent on the presence of a TATA box. Promoters whose accurate transcription is directed by a pyrimidine-rich initiator element, however, are immune to the effects of p53. Furthermore, we observe that repression is mediated by an interaction of p53 with basal transcription factor(s). Thus, p53 appears to repress the activity of certain promoters through direct communication with TATA box-dependent basal transcription machinery.
Insights
The tumor suppressor protein p53 inhibits gene transcription. Wild-type p53 specifically represses TATA box-dependent promoters by interacting with transcription factors.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- The p53 protein is a critical tumor suppressor frequently mutated in human cancers.
- Wild-type p53 inhibits oncogene-induced transformation and can mediate growth arrest.
- p53's normal function includes activating gene expression via DNA-binding sequences.
Purpose of the Study:
- To investigate the mechanism by which p53 represses gene transcription.
- To determine if p53's repressive activity is promoter-specific.
- To identify the molecular interactions involved in p53-mediated transcriptional repression.
Main Methods:
- In vivo and in vitro expression studies.
- Analysis of promoter activity using TATA box and initiator element-dependent promoters.
- Co-immunoprecipitation assays to detect protein interactions.
Main Results:
- Wild-type p53 specifically represses promoters dependent on a TATA box for initiation.
- Promoters utilizing a pyrimidine-rich initiator element are unaffected by p53.
- p53-mediated repression involves direct interaction with basal transcription factors.
Conclusions:
- p53 acts as a transcriptional repressor for a subset of promoters.
- The repression mechanism involves targeting the TATA box-dependent transcription machinery.
- These findings elucidate a novel mechanism of p53 tumor suppressor function.