Endogenous p53 expression in human and mouse is not regulated by its 3′UTR

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Abstract

The TP53 gene encodes the tumor suppressor p53 which is functionally inactivated in many human cancers. Numerous studies suggested that 3′UTR-mediated p53 expression regulation plays a role in tumorigenesis and could be exploited for therapeutic purposes. However, these studies did not investigate post-transcriptional regulation of the native TP53 gene. Here, we used CRISPR/Cas9 to delete the human and mouse TP53/Trp53 3′UTRs while preserving endogenous mRNA processing. This revealed that the endogenous 3′UTR is not involved in regulating p53 mRNA or protein expression neither in steady state nor after genotoxic stress. Using reporter assays, we confirmed the previously observed repressive effects of the isolated 3′UTR. However, addition of the TP53 coding region to the reporter had a dominant negative impact on expression as its repressive effect was stronger and abrogated the contribution of the 3′UTR. Our data highlight the importance of genetic models in the validation of post-transcriptional gene regulatory effects.

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All data generated or analyzed during this study are included in the manuscript and supporting files.

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Sibylle Mitschka

Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Christine Mayr

Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

For correspondence
mayrc@mskcc.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7084-7608

Funding

NIH Office of the Director (DP1-GM123454)

Christine Mayr

Pershing Square Sohn Cancer Research Alliance

Christine Mayr

National Cancer Institute (P30 CA008748)

Christine Mayr

Deutsche Forschungsgemeinschaft

Sibylle Mitschka

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#18-07-010) of Memorial Sloan Kettering Cancer Center. All procedures were approved by the Institutional Animal Care and Use Committee at MSKCC under protocol #18-07-010.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.