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Tumor Dormancy, Quiescence, and Senescence, Vol. 3 pp 113–122Cite as

Regulation of the Promyelocytic Leukemia Protein and Its Role in Premature Senescence

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Part of the book series: Tumor Dormancy and Cellular Quiescence and Senescence ((DOQU,volume 3))

Abstract

Premature senescence functions as a tumor suppressor mechanism in response to oncogenic stimuli. It is characterized by irreversible cell cycle arrest mediated by tumor suppressors such as p53, Rb and the Promyelocytic Leukemia (PML) protein. PML mainly localizes in sub-nuclear structures known as PML nuclear bodies. These nuclear bodies accumulate in senescent cells largely due to increased PML gene transcription driven by p53 and/or the interferon pathways. PML exerts its pro-senescence activity by modulating both the p53 and Rb pathways, the major regulators of the cellular senescence program. Mechanistically, PML binds and promotes p53 modifications to generate a positive feedback loop, thereby triggering the senescence program. In addition, PML associates with Rb and may function in Rb/E2F-mediated gene silencing in senescent cells. Moreover, PML bodies recruit DNA damage sensing and repair proteins, thereby linking PML to the activation of the DNA damage response pathway, a pathway frequently activated in senescence. Therefore, elucidation of key factors controlling PML protein abundance will help to better understand how cells become transformed by avoiding senescence and allowing continued cellular proliferation in the presence of oncogenic signals. These findings will also be crucial in aiding scientists and physicians in the development of novel anti-cancer therapies by restoring PML to trigger senescence.

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Acknowledgement

This work was supported in part by a NRSA T32 training grant to AET and by NIH grants (GM089763 and GM094777) to WW.

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Authors and Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    Alan W. Lau, Adriana E. Tron & Wenyi Wei

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  1. Alan W. Lau
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  2. Adriana E. Tron
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  3. Wenyi Wei
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Correspondence to Wenyi Wei .

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  1. Department of Biological Sciences, Kean University, Union, New Jersey, USA

    M.A. Hayat

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Lau, A.W., Tron, A.E., Wei, W. (2014). Regulation of the Promyelocytic Leukemia Protein and Its Role in Premature Senescence. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Vol. 3. Tumor Dormancy and Cellular Quiescence and Senescence, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9325-4_9

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