P53 must be competent for transcriptional regulation to suppress tumor formation

ABSTRACT _In vitro_ studies suggest that effective tumor suppression by p53 requires multiple domains to execute transcription-dependent and transcription-independent functions. We generated

a mutant _p53_ allele in mice, _p53__W25QL26S_ (_p53__QS_), containing an inactive transactivation domain to evaluate the importance of transactivation for p53-mediated tumor suppression.

Recently, we discovered that the allele also contains a valine substitution for alanine at codon 135, which borders the DNA-binding domain. We found that p53QSval135 bound to chromatin

albeit less well than p53QSala135, but both were equally deficient in transcriptional regulation, apoptosis induction in mouse embryo fibroblasts (MEFs), and suppression of tumor formation

by E1A, Ha-Ras transformed MEFs. _p53__QSval135_ mice and _p53-_null mice exhibited identical tumor development kinetics and spectra in spontaneous and oncogene-initiated tumorigenicity

assays, when tested in a homo- and heterozygous configuration. The _p53__QSval135_ allele did not have dominant negative functions and behaved as a null allele. Taken together, these data

indicate that effective tumor suppression requires the transcriptional regulation function of p53, and they suggest that transactivation independent functions of p53 are unlikely to

contribute significantly to tumor suppression _in vivo_. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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THE PARADIGMS FOR TUMOR SUPPRESSION: LESSONS FROM THE P53 FIELD Article 08 June 2021 ACQUISITION OF ANEUPLOIDY DRIVES MUTANT P53-ASSOCIATED GAIN-OF-FUNCTION PHENOTYPES Article Open access 31

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Wilson SH and Prives C . (2001). _EMBO J._, 20, 914–923. * Zhu J, Jiang J, Zhou W, Zhu K and Chen X . (1999). _Oncogene_, 18, 2149–2155. Download references ACKNOWLEDGEMENTS We thank Dr

Franck Toledo for identifying the third mutation, val135, in the _p53__QS_-targeting construct, Mrs Marianne Kastemar for technical assistance, and Drs Franck Toledo, Jayne Stommel, and Kurt

Kummel for critical comments on the manuscript. This work was supported by the Swedish Cancer Society (MN), the Swedish Childhood Cancer Fund (MN) and Erik, Karin och Gösta Selanders

Stiftelse (MN), and the NIH (CA61449, GW and CA046283, TVD). AUTHOR INFORMATION Author notes * Xinrong Hu Present address: Department of Pathology, Guangdong Medical College, Zhanjiang City,

Guangdong Province, 524023, P.R. China * Monica Nistér and Mengjia Tang: These authors share first authorship. * Xiao-Qun Zhang, Chaoying Yin and Michelle Beeche: These three authors

contributed equally to this work AUTHORS AND AFFILIATIONS * Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital, 171 76, Stockholm, Sweden

Monica Nistér * Gene Expression Laboratory, The Salk Institute, La Jolla, CA, 92037, USA Mengjia Tang, Michelle Beeche & Geoffrey M Wahl * Department of Genetics and Pathology, Rudbeck

Laboratory, University of Uppsala, 751 85, Uppsala, Sweden Monica Nistér, Xiao-Qun Zhang & Xinrong Hu * Department of Genetics, University of North Carolina at Chapel Hill, NC, 27599,

USA Chaoying Yin & Terry van Dyke * Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, University of Uppsala, 751 85, Uppsala, Sweden Gunilla Enblad Authors *

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Correspondence to Geoffrey M Wahl. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc) SUPPLEMENTARY INFORMATION

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RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Nistér, M., Tang, M., Zhang, XQ. _et al._ p53 must be competent for transcriptional regulation to

suppress tumor formation. _Oncogene_ 24, 3563–3573 (2005). https://doi.org/10.1038/sj.onc.1208354 Download citation * Received: 31 August 2004 * Revised: 25 October 2004 * Accepted: 25

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initiative KEYWORDS * p53 * transactivation * DNA binding * apoptosis * tumor suppression