Abstract
The tumor suppressor gene p53 is a transcription factor that mediates both cell cycle arrest and apoptosis. Interestingly, p53 also induces differentiation of a number of tissues, including leukemic cells. However, although p53-mediated differentiation of leukemic U-937 cells depends on the transcriptional activity of p53, a p53 target gene mediating differentiation has hitherto not been identified. To screen for novel p53 target genes in leukemic cells, a cDNA microarray analysis was performed with U-937-4/ptsp53 cells, expressing a temperature-sensitive p53 mutant. We report that transcription of the Staf50 (stimulated transacting factor of 50 kDa) gene is upregulated in response to wild-type p53 in U-937-4, K562 and MCF-7 cells. Staf50 was directly activated by p53, as determined by the independence of de novo protein synthesis. Moreover, while the proximal promoter of Staf50 was found not to be p53 responsive, a functional enhancer-like p53-response element in intron 1 of the Staf50 gene was identified that was also transactivated by the p53-family member p73. Direct binding of p53 to the response element was shown by electrophoretic mobility shift analysis. Ectopic expression of Staf50 in U-937 cells resulted in reduced clonogenic growth. Moreover, levels of endogenous Staf50 mRNA correlated to all-trans retinoic acid-induced differentiation of promyelocytic NB-4 and HL60 cells, suggesting that Staf50 could be involved in proliferation and/or differentiation of leukemic cells.
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Acknowledgements
We are indebted to Dr Tor Olofsson for invaluable help with cell sorting. This work was supported by grants from the Swedish Cancer Society, the Swedish Research Council (Project #11546), the Swedish Childhood Cancer Foundation, the Georg Danielsson Foundation, the Gunnar Nilsson Cancer Foundation, the John and Augusta Persson Foundation, the Lundberg Foundation, the Tornspiran Foundation, the Greta and Johan Kock Foundation, funding from Lund University Hospital and from the Knut and Alice Wallenberg Foundation through the SWEGENE program.
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Obad, S., Brunnström, H., Vallon-Christersson, J. et al. Staf50 is a novel p53 target gene conferring reduced clonogenic growth of leukemic U-937 cells. Oncogene 23, 4050–4059 (2004). https://doi.org/10.1038/sj.onc.1207524
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DOI: https://doi.org/10.1038/sj.onc.1207524
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