2. Academic Validation
  3. Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4

Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4

  • Science. 2015 Jun 5;348(6239):1155-60. doi: 10.1126/science.aaa5111.
Yao Liang Wong 1,  John V Anzola 2,  Robert L Davis 2,  Michelle Yoon 2,  Amir Motamedi 2,  Ashley Kroll 1,  Chanmee P Seo 2,  Judy E Hsia 2,  Sun K Kim 3,  Jennifer W Mitchell 3,  Brian J Mitchell 3,  Arshad Desai 1,  Timothy C Gahman 2,  Andrew K Shiau 4,  Karen Oegema 5
Affiliations

Affiliations

  • 1 Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
  • 2 Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
  • 3 Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 4 Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA. koegema@ucsd.edu ashiau@ucsd.edu.
  • 5 Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. koegema@ucsd.edu ashiau@ucsd.edu.
PMID: 25931445 DOI: 10.1126/science.aaa5111
Abstract

Centrioles are ancient organelles that build centrosomes, the major microtubule-organizing centers of animal cells. Extra centrosomes are a common feature of Cancer cells. To investigate the importance of centrosomes in the proliferation of normal and Cancer cells, we developed centrinone, a reversible inhibitor of Polo-like kinase 4 (PLK4), a serine-threonine protein kinase that initiates centriole assembly. Centrinone treatment caused centrosome depletion in human and other vertebrate cells. Centrosome loss irreversibly arrested normal cells in a senescence-like G1 state by a p53-dependent mechanism that was independent of DNA damage, stress, Hippo signaling, extended mitotic duration, or segregation errors. In contrast, Cancer cell lines with normal or amplified centrosome numbers could proliferate indefinitely after centrosome loss. Upon centrinone washout, each Cancer cell line returned to an intrinsic centrosome number "set point." Thus, cells with cancer-associated mutations fundamentally differ from normal cells in their response to centrosome loss.

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