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Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition

Oncogene volume 28, pages 824–831 (2009)Cite this article

Abstract

Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3β phosphorylation at Ser9, stabilization and nuclear localization of β-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27Kip1 phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27Kip1 phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.

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Acknowledgements

This work was supported by a Korea Research Foundation Grant (KRF-2007-314-E00041) funded by the Korean Government (MOEHRD, Basic Research Promotion Fund).

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  1. J-Y Lee and M-B Kang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea

    J-Y Lee, M-B Kang, S-H Jang, T Qian, H-J Kim & G Kong

  2. Department of Biological Sciences, Sungkyunkwan University, Kyunggi-Do, Republic of Korea

    C-H Kim

  3. Department of Biochemistry, College of Medicine, Hanyang University, Seoul, Republic of Korea

    Y Kim

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  1. J-Y Lee
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Correspondence to G Kong.

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Lee, JY., Kang, MB., Jang, SH. et al. Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition. Oncogene 28, 824–831 (2009). https://doi.org/10.1038/onc.2008.451

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  • DOI: https://doi.org/10.1038/onc.2008.451

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