Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt (original) (raw)

Oncogene volume 18, pages 7328–7333 (1999)Cite this article

Abstract

Akt, a proto-oncogene that encodes a cytosolic serine/threonine kinase, can phosphorylate and modulate the activity of several proteins involved in cellular metabolism and survival. Recently, two mammalian highly related forkhead transcription factors FKHRL1 and AFX and their nematode homologue Daf-16 have been found to be targets of this kinase. Here we show that Akt, but not inactive Akt, represses the transcriptional activity of FKHR, another member of the forkhead family. FKHR mutants with alanine substitutions at three Akt phosphorylation consensus sites (T24, S256 and S319) were inhibited by Akt, but mutation of all three sites rendered FKHR resistant to suppression. By contrast, the transcriptional activity of the oncogenic PAX3 – FKHR fusion protein, containing two consensus phosphorylation sites, was not inhibited by Akt. Importantly, Akt inhibited the translocation of FKHR to the nucleus, providing a mechanism by which Akt might regulate the transcriptional activity of FKHR. Consistent with this model, the localization of the PAX3 – FKHR fusion protein was nuclear and was not altered by Akt. These results provide evidence that Akt inhibits the transcriptional activity of FKHR by controlling its trafficking into the nucleus and that oncogenic PAX3 – FKHR can escape this negative regulation by Akt.

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Acknowledgements

We thank Y Hu, N Inohara and MA Benedict for critical review of the manuscript and experimental suggestions. We thank BA Hemmings and TF Franke for Akt plasmids. G Núñez is a recipient of a Research Career Development Award CA-64421 from the National Institutes of Health. The research was supported by a grant from the JP McCarthy Foundation to G Núñez. L dePeso was supported by a training grant from the University of Michigan/NCI Program. VM González was supported by a Fellowship from the Spanish Ministry of Education and Science. R Hernández was supported by the NIH grant #P01-CA75136-01A1. FG Barr was supported by the NIH grant #R01-CA64202.

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Authors and Affiliations

  1. Department of Pathology, The University of Michigan Medical School, Ann Arbor, 48109, Michigan, MI, USA
    Luis del Peso, Víctor M González & Gabriel Núñez
  2. Department of Internal Medicine, Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, 48109, Michigan, MI, USA
    Rubén Hernández
  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania PA, USA
    Frederic G Barr

Authors

  1. Luis del Peso
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  2. Víctor M González
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  3. Rubén Hernández
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  4. Frederic G Barr
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  5. Gabriel Núñez
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del Peso, L., González, V., Hernández, R. et al. Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt.Oncogene 18, 7328–7333 (1999). https://doi.org/10.1038/sj.onc.1203159

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