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GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis
GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis
The primary role of the Hdm2/Mdm2 oncoprotein is to regulate the levels and activity of the transcription factor p53. Hdm2 synthesis is itself tightly controlled and, as demonstrated by a recently described SNP (SNP309) in the hdm2-P2 promoter, minor variations in Hdm2 expression have phenotypic consequences on radiation sensitivity and cancer predisposition. To further define mechanisms regulating Hdm2 expression, we have investigated the effects of the GC-selective DNA-binding drug, Mithramycin A (MA) on hdm2 mRNA transcription, trafficking, and translation. Firstly we show that the constitutive hdm2-P1 promoter is inhibited by MA. We define, for the first time, the minimal sequence elements that are required for P1-promoter activity and identify those which confer MA sensitivity. Secondly, MA induces p53-dependent transcription from the hdm2-P2 promoter. Thirdly, and critically, MA also inhibits Hdm2 synthesis at the post-transcriptional level, with negative effects on hdm2 mRNA nuclear export and translation. This study highlights the complex interplay between the pathways that regulate Hdm2 protein synthesis in cancer cells, and furthermore emphasizes the export of hdm2 mRNA from the nucleus to the cytoplasm as a key point of control in this process.

transcription, hdm2, messenger-rna export, p53, dna-binding, single nucleotide polymorphism, embryonic lethality, promoter, cells, feedback loop, protein, nuclear export, mrna export, open reading frames, mdm2 expression, mdm2-deficient mice, oncogene mdm2, cancer, expression, mdm2
0950-9232
4183-4193
Phillips, A.
3f6d00b5-fb3c-423b-976d-83f22a2dc47b
Darley, M.
7be23780-a781-4dd4-a74c-f5affbb79521
Blaydes, J.P.
e957f999-fd91-4f77-ad62-5b4ef069b15b
Phillips, A.
3f6d00b5-fb3c-423b-976d-83f22a2dc47b
Darley, M.
7be23780-a781-4dd4-a74c-f5affbb79521
Blaydes, J.P.
e957f999-fd91-4f77-ad62-5b4ef069b15b

Phillips, A., Darley, M. and Blaydes, J.P. (2006) GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis. Oncogene, 25 (30), 4183-4193. (doi:10.1038/sj.onc.1209451).

Record type: Article

Abstract

The primary role of the Hdm2/Mdm2 oncoprotein is to regulate the levels and activity of the transcription factor p53. Hdm2 synthesis is itself tightly controlled and, as demonstrated by a recently described SNP (SNP309) in the hdm2-P2 promoter, minor variations in Hdm2 expression have phenotypic consequences on radiation sensitivity and cancer predisposition. To further define mechanisms regulating Hdm2 expression, we have investigated the effects of the GC-selective DNA-binding drug, Mithramycin A (MA) on hdm2 mRNA transcription, trafficking, and translation. Firstly we show that the constitutive hdm2-P1 promoter is inhibited by MA. We define, for the first time, the minimal sequence elements that are required for P1-promoter activity and identify those which confer MA sensitivity. Secondly, MA induces p53-dependent transcription from the hdm2-P2 promoter. Thirdly, and critically, MA also inhibits Hdm2 synthesis at the post-transcriptional level, with negative effects on hdm2 mRNA nuclear export and translation. This study highlights the complex interplay between the pathways that regulate Hdm2 protein synthesis in cancer cells, and furthermore emphasizes the export of hdm2 mRNA from the nucleus to the cytoplasm as a key point of control in this process.

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More information

Published date: 13 July 2006
Keywords: transcription, hdm2, messenger-rna export, p53, dna-binding, single nucleotide polymorphism, embryonic lethality, promoter, cells, feedback loop, protein, nuclear export, mrna export, open reading frames, mdm2 expression, mdm2-deficient mice, oncogene mdm2, cancer, expression, mdm2

Identifiers

Local EPrints ID: 26525
URI: http://eprints.soton.ac.uk/id/eprint/26525
ISSN: 0950-9232
PURE UUID: 492e486c-f78d-48ad-bdea-a20f8906ccb7
ORCID for J.P. Blaydes: ORCID iD orcid.org/0000-0001-8525-0209

Catalogue record

Date deposited: 10 Apr 2006
Last modified: 29 Oct 2019 01:56

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Contributors

Author: A. Phillips
Author: M. Darley
Author: J.P. Blaydes ORCID iD

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