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

Oncogene
A PhillipsJeremy P Blaydes

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...Continue Reading

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Citations

Nov 16, 2010·Molecular Cancer Therapeutics·Hongbo WangChunhong Yan
Sep 11, 2008·British Journal of Cancer·M DimitriadiV P Collins
Jun 5, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Marta Sanchez-CarbayoCarlos Cordon-Cardo
Apr 27, 2021·Frontiers in Cell and Developmental Biology·Annapaola AngrisaniEnrico De Smaele

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