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  • Original Paper
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p53 must be competent for transcriptional regulation to suppress tumor formation

Oncogene volume 24, pages 3563–3573 (2005)Cite this article

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, p53W25QL26S (p53QS), 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. p53QSval135 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 p53QSval135 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.

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Acknowledgements

We thank Dr Franck Toledo for identifying the third mutation, val135, in the p53QS-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).

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Author notes

  1. Xinrong Hu

    Present address: Department of Pathology, Guangdong Medical College, Zhanjiang City, Guangdong Province, 524023, P.R. China

  2. Monica Nistér and Mengjia Tang: These authors share first authorship.

  3. Xiao-Qun Zhang, Chaoying Yin and Michelle Beeche: These three authors contributed equally to this work

Authors and Affiliations

  1. Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital, 171 76, Stockholm, Sweden

    Monica Nistér

  2. Gene Expression Laboratory, The Salk Institute, La Jolla, CA, 92037, USA

    Mengjia Tang, Michelle Beeche & Geoffrey M Wahl

  3. Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, 751 85, Uppsala, Sweden

    Monica Nistér, Xiao-Qun Zhang & Xinrong Hu

  4. Department of Genetics, University of North Carolina at Chapel Hill, NC, 27599, USA

    Chaoying Yin & Terry van Dyke

  5. Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, University of Uppsala, 751 85, Uppsala, Sweden

    Gunilla Enblad

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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

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