Nucleic Acids Research Advance Access originally published online on November 10, 2008
Nucleic Acids Research 2008 36(22):7168-7180; doi:10.1093/nar/gkn888
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Nucleic Acids Research, 2008, Vol. 36, No. 22 7168-7180
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Induction of PPM1D following DNA-damaging treatments through a conserved p53 response element coincides with a shift in the use of transcription initiation sites
1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 and 2Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA
* To whom correspondence should be addressed. Tel: +1 301 435 6293; Fax: +1 301 435 8188; Email: mazurs{at}mail.nih.gov
Received January 14, 2008. Revised September 14, 2008. Accepted October 20, 2008.
PPM1D (Wip1), a type PP2C phosphatase, is expressed at low levels in most normal tissues but is overexpressed in several types of cancers. In cells containing wild-type p53, the levels of PPM1D mRNA and protein increase following exposure to genotoxic stress, but the mechanism of regulation by p53 was unknown. PPM1D also has been identified as a CREB-regulated gene due to the presence of a cyclic AMP response element (CRE) in the promoter. Transient transfection and chromatin immunoprecipitation experiments in HCT116 cells were used to characterize a conserved p53 response element located in the 5' untranslated region (UTR) of the PPM1D gene that is required for the p53-dependent induction of transcription from the human PPM1D promoter. CREB binding to the CRE contributes to the regulation of basal expression of PPM1D and directs transcription initiation at upstream sites. Following exposure to ultraviolet (UV) or ionizing radiation, the abundance of transcripts with short 5' UTRs increased in cells containing wild-type p53, indicating increased utilization of downstream transcription initiation sites. In cells containing wild-type p53, exposure to UV resulted in increased PPM1D protein levels even when PPM1D mRNA levels remained constant, indicating post-transcriptional regulation of PPM1D protein levels.
Present addresses: Matteo Rossi, Istituto Toscano Tumori, Via Fiorentina 1, 53100 Siena, Italy
Oleg N. Demidov, Institute of Molecular and Cell Biology, 61 Bioplis Drive, Proteos, 138673, Singapore
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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