Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex

  1. Pavan Kumar P.
  2. Uchenna Emechebe
  3. Richard Smith
  4. Sarah Franklin
  5. Barry Moore
  6. Mark Yandell
  7. Stephen L Lessnick
  8. Anne M Moon  Is a corresponding author
  1. Weis Center for Research, Geisinger Clinic, United States
  2. University of Utah, United States
  3. Huntsman Cancer Institute, University of Utah, United States
  4. Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, United States

Abstract

Cellular senescence is a crucial tumor suppressor mechanism. We discovered a CAPERα/TBX3 repressor complex required to prevent senescence in primary cells and mouse embryos. Critical, previously unknown roles for CAPERα in controlling cell proliferation are manifest in an obligatory interaction with TBX3 to regulate chromatin structure and repress transcription of CDKN2A-p16INK and the RB pathway. The IncRNA UCA1 is a direct target of CAPERα/TBX3 repression whose overexpression is sufficient to induce senescence. In proliferating cells, we found that hnRNPA1 binds and destabilizes CDKN2A-p16INK mRNA whereas during senescence, UCA1 sequesters hnRNPA1 and thus stabilizes CDKN2A-p16INK. Thus CAPERα/TBX3 and UCA1 constitute a coordinated, reinforcing mechanism to regulate both CDKN2A-p16INK transcription and mRNA stability. Dissociation of the CAPERα/TBX3 co-repressor during oncogenic stress activates UCA1, revealing a novel mechanism for oncogene-induced senescence. Our elucidation of CAPERα and UCA1 functions in vivo provides new insights into senescence induction, and the oncogenic and developmental properties of TBX3.

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Author details

  1. Pavan Kumar P.

    Weis Center for Research, Geisinger Clinic, Danville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Uchenna Emechebe

    University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Richard Smith

    Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sarah Franklin

    Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Barry Moore

    University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Mark Yandell

    University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephen L Lessnick

    Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Anne M Moon

    Weis Center for Research, Geisinger Clinic, Danville, United States
    For correspondence
    ammoon@geisinger.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Version history

  1. Received: March 16, 2014
  2. Accepted: May 22, 2014
  3. Accepted Manuscript published: May 29, 2014 (version 1)
  4. Version of Record published: July 1, 2014 (version 2)

Copyright

© 2014, Kumar P. et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Pavan Kumar P.
  2. Uchenna Emechebe
  3. Richard Smith
  4. Sarah Franklin
  5. Barry Moore
  6. Mark Yandell
  7. Stephen L Lessnick
  8. Anne M Moon
(2014)
Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex
eLife 3:e02805.
https://doi.org/10.7554/eLife.02805

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https://doi.org/10.7554/eLife.02805

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