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A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

Nature volume 465, pages 1033–1038 (2010)Cite this article

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Abstract

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.

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Figure 1: PTENP1 is targeted by PTEN -targeting miRNAs.
Figure 2: PTENP1 3′ UTR exerts a tumour suppressive function by acting as a decoy for PTEN -targeting miRNAs.
Figure 3: Loss of PTENP1 in cancer.
Figure 4: PTEN 3′ UTR and KRAS1P 3′ UTR function as decoys and a general model for endogenous miRNA decoy mechanism.

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Acknowledgements

We thank Pandolfi laboratory members for critical discussions, in particular A. Carracedo for critical input; S. Feng for technical assistance. We thank B. Vogelstein for DICER−/− cells; T. Yuan for assistance with FACS analysis; A. Tuccoli for assistance with miRNA RT–PCR; I. Osman for support and suggestions. L.P. was supported by fellowships from the Istituto Toscano Tumori and the American Italian Cancer Foundation. L.S. was supported by fellowships from the Human Frontier Science Program and the Canadian Institutes of Health Research. This work was supported by NIH grant R01 CA-82328-09 to P.P.P.

Author information

Author notes

  1. Laura Poliseno

    Present address: Present address: Department of Dermatology, New York University Medical Center, New York, New York 10016, USA.,

  2. Laura Poliseno and Leonardo Salmena: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Medicine and Pathology, Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA,

    Laura Poliseno, Leonardo Salmena, William J. Haveman & Pier Paolo Pandolfi

  2. FAS Research Computing & FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA,

    Jiangwen Zhang

  3. Department of Surgery, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA,

    Brett Carver

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Contributions

P.P.P. spearheaded and supervised the project; L.P., L.S. and P.P.P. designed experiments; L.P., L.S. and W.J.H. performed experiments; B.C. provided prostate cancer patient sample cDNAs. J.Z. performed all bioinformatic analyses. L.P., L.S. and P.P.P. analysed the data and wrote the paper. All authors critically discussed the results and the manuscript.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

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The authors declare no competing financial interests.

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Poliseno, L., Salmena, L., Zhang, J. et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033–1038 (2010). https://doi.org/10.1038/nature09144

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