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Full-length hdmX transcripts decrease following genotoxic stress

Oncogene volume 27, pages 6657–6666 (2008)Cite this article

Abstract

Previous studies have suggested that the mdmX gene is constitutively transcribed, and that MdmX protein activity is instead controlled by cellular localization and DNA damage induced Mdm2-mediated ubiquitination leading to proteasomal degradation. In these studies, we report that the human mdmX (hdmX) mRNA is reproducibly decreased in various human cell lines following treatment with various DNA-damaging agents. Repression of hdmX transcripts is observed in DNA-damaged HCT116 colon cancer cells and in isogenic p53−/− cells, suggesting that this effect is p53-independent. Reduction in the amount of hdmX transcript occurs in both human tumor cell lines and primary human diploid fibroblasts, and results in a significant reduction of HdmX protein. Examination of hdmX promoter activity suggests that damage-induced repression of hdmX mRNA is not significantly impacted by transcription initiation. In contrast, changes in hdmX mRNA splicing appear to partly explain the reduction in full-length hdmX mRNA levels in tumor cell lines with the destabilization of full-length hdmX transcripts, potentially through microRNA miR-34a regulation, also impacting transcript levels. Taken together, this study uncovers previously unrecognized cellular mechanisms by which hdmX mRNA levels are kept low following genotoxic stress.

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Acknowledgements

We thank members of the Berberich laboratory for their insightful discussions. This work was supported by NIH CA66430 (to SJB).

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  1. Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA

    M Markey & S J Berberich

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  1. M Markey
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Correspondence to S J Berberich.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Markey, M., Berberich, S. Full-length hdmX transcripts decrease following genotoxic stress. Oncogene 27, 6657–6666 (2008). https://doi.org/10.1038/onc.2008.266

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