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

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  • Laura Poliseno

    (Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Present address: Department of Dermatology, New York University Medical Center, New York, New York 10016, USA.)

  • Leonardo Salmena

    (Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA)

  • Jiangwen Zhang

    (FAS Research Computing & FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA)

  • Brett Carver

    (Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA)

  • William J. Haveman

    (Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA)

  • Pier Paolo Pandolfi

    (Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA)

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.

Suggested Citation

  • Laura Poliseno & Leonardo Salmena & Jiangwen Zhang & Brett Carver & William J. Haveman & Pier Paolo Pandolfi, 2010. "A coding-independent function of gene and pseudogene mRNAs regulates tumour biology," Nature, Nature, vol. 465(7301), pages 1033-1038, June.
    • Handle: RePEc:nat:nature:v:465:y:2010:i:7301:d:10.1038_nature09144
    DOI: 10.1038/nature09144
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    Cited by:

    1. Federica Conte & Giulia Fiscon & Matteo Chiara & Teresa Colombo & Lorenzo Farina & Paola Paci, 2017. "Role of the long non-coding RNA PVT1 in the dysregulation of the ceRNA-ceRNA network in human breast cancer," PLOS ONE, Public Library of Science, vol. 12(2), pages 1-22, February.
    2. Elliot H. Akama-Garren & Theo Broek & Lea Simoni & Carlos Castrillon & Cees E. Poel & Michael C. Carroll, 2021. "Follicular T cells are clonally and transcriptionally distinct in B cell-driven mouse autoimmune disease," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    3. J. Patrick Malone, 2012. "The Systems Theory of Autistogenesis," SAGE Open, , vol. 2(2), pages 21582440124, April.
    4. Antonios Apostolopoulos & Naohiro Kawamoto & Siu Yu A. Chow & Hitomi Tsuiji & Yoshiho Ikeuchi & Yuichi Shichino & Shintaro Iwasaki, 2024. "dCas13-mediated translational repression for accurate gene silencing in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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