Publication Date:
2015-05-02
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764081/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764081/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wong, Yao Liang -- Anzola, John V -- Davis, Robert L -- Yoon, Michelle -- Motamedi, Amir -- Kroll, Ashley -- Seo, Chanmee P -- Hsia, Judy E -- Kim, Sun K -- Mitchell, Jennifer W -- Mitchell, Brian J -- Desai, Arshad -- Gahman, Timothy C -- Shiau, Andrew K -- Oegema, Karen -- GM074207/GM/NIGMS NIH HHS/ -- GM089970/GM/NIGMS NIH HHS/ -- GM103403/GM/NIGMS NIH HHS/ -- R01 GM089970/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1155-60. doi: 10.1126/science.aaa5111. Epub 2015 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. ; Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA. ; Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. ; Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA. koegema@ucsd.edu ashiau@ucsd.edu. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25931445" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line, Tumor
;
Cell Proliferation
;
Centrioles/*drug effects
;
Humans
;
Mice
;
Piperazines/pharmacology
;
Protein Kinase Inhibitors/chemistry/*pharmacology
;
Protein-Serine-Threonine Kinases/*antagonists & inhibitors
;
Pyrimidines/chemistry/*pharmacology
;
Sulfones/chemistry/*pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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