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Regulation of c-Met-dependent gene expression by PTEN

Oncogene volume 23, pages 9173–9182 (2004)Cite this article

Abstract

Receptor tyrosine kinases (RTK) and the tumor suppressor PTEN co-regulate oncogenic cell signaling pathways. How these interactions influence gene transcription is inadequately understood. We used expression microarrays to investigate the effects of PTEN on gene expression changes caused by activating c-Met in human glioblastoma cells. c-Met activation by scatter factor/hepatocyte growth factor (SF/HGF) altered the expression of 27-fold more genes in PTEN-null U-373MG cells than in PTEN homozygous primary normal human astrocytes (523 vs 19 genes). Restoring wt-PTEN in U-373MG cells dramatically altered patterns of c-Met regulated gene expression. This effect was varied depending on the specific gene in question. PTEN reduced the number of c-Met regulated transcripts from 931 to 502, decreased the relative number of genes upregulated by c-Met from 46 to 25%, and increased the relative number of downregulated genes from 54 to 75%. PTEN and c-Met co-regulated many genes involved in cell growth regulation such as oncogenes, growth factors, transcription factors, and constituents of the ubiquitin pathway. c-Met activation in PTEN-null (but not PTEN reconstituted) cells led to upregulation of the EGFR agonist TGFα and subsequently to EGFR activation. Using PTEN mutants, we found that PTEN's transcriptional effects were either lipid-phosphatase dependent, protein-phosphatase dependent, or phosphatase-independent. These results show that PTEN has critical and mechanistically complex effects on RTK-regulated gene transcription. These findings expand our understanding of tumor promoter/suppressor inter-relationships and downstream transcriptional effects of PTEN loss and c-Met overexpression in malignant gliomas.

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Acknowledgements

Supported by NIH RO1 Grant NS045209 (Roger Abounader) and NIH ROI Grants NS032148 and NS43987 (John Laterra).

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Authors and Affiliations

  1. Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Roger Abounader & John Laterra

  2. Kennedy Krieger Research Institute, Baltimore, MD, USA

    Roger Abounader, Thomas Reznik & John Laterra

  3. Department of Neurosciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Carlo Colantuoni & John Laterra

  4. Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Francisco Martinez-Murillo

  5. Department of Oncology, Lombardi Cancer Center, Washington, DC, USA

    Eliot M Rosen

  6. Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    John Laterra

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  1. Roger Abounader
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  2. Thomas Reznik
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  3. Carlo Colantuoni
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  4. Francisco Martinez-Murillo
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  5. Eliot M Rosen
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  6. John Laterra
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Correspondence to Roger Abounader or John Laterra.

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Abounader, R., Reznik, T., Colantuoni, C. et al. Regulation of c-Met-dependent gene expression by PTEN. Oncogene 23, 9173–9182 (2004). https://doi.org/10.1038/sj.onc.1208146

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