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PU.1 binding to the p53 family of tumor suppressors impairs their transcriptional activity

Abstract

The transcription factor PU.1 is essential for terminal myeloid differentiation, B- and T-cell development, erythropoiesis and hematopoietic stem cell maintenance. PU.1 functions as oncogene in Friend virus-induced erythroleukemia and as tumor suppressor in acute myeloid leukemias. Moreover, Friend virus-induced erythroleukemia requires maintenance of PU.1 expression and the disruption of p53 function greatly accelerates disease progression. It has been hypothesized that p53-mediated expression of the p21Cip1 cell cycle inhibitor during differentiation of pre-erythroleukemia cells promotes selection against p53 function. In addition to the blockage of erythroblast differentiation provided by increased levels of PU.1, we propose that PU.1 alters p53 function. We demonstrate that PU.1 reduces the transcriptional activity of the p53 tumor suppressor family and thus inhibits activation of genes important for cell cycle regulation and apoptosis. Inhibition is mediated through binding of PU.1 to the DNA-binding and/or oligomerization domains of p53/p73 proteins. Lastly, knocking down endogenous PU.1 in p53 wild-type REH B-cell precursor leukemia cells leads to increased expression of the p53 target p21Cip1.

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Acknowledgements

We thank Drs C Prives, A Villunger and M Loeffler for providing plasmids. This work was supported by grants from the National Institutes of Health DK49886 and AI49165, The Stein Endowment Fund and The Joyce Klein Stock Gift (to BET); the Swiss National Science Foundation 3100A0-112385 (to MFF) and 3100A0-118276 (to MPT), the Marlies-Schwegler Foundation and the Bernese Foundation of Cancer Research (to MFF). MPT is a recipient of fellowships from the Swiss National Foundation (84NP-057502), the Swiss Federation against Cancer (no. BIL OCS–01198-09-2001) and the Bernese Cancer League.

Authors' contribution: MPT performed project design, collection and analysis of all data, and manuscript writing. VAR performed in vitro protein interaction assays and reviewed manuscript. RA and GA performed in vivo protein interaction and RNA interference assays and reviewed manuscript. BET and MFF contributed toward project planning and design, data analysis and manuscript writing.

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Correspondence to B E Torbett.

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This is publication 18417-MEM from The Scripps Research Institute.

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Tschan, M., Reddy, V., Ress, A. et al. PU.1 binding to the p53 family of tumor suppressors impairs their transcriptional activity. Oncogene 27, 3489–3493 (2008). https://doi.org/10.1038/sj.onc.1211004

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  • DOI: https://doi.org/10.1038/sj.onc.1211004

Keywords

  • PU.1
  • p53
  • p73
  • transcriptional repression

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