| Protein farnesylation inhibitors cause donut-shaped cell nuclei attributable to a centrosome separation defect. | |
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MedLine Citation:
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PMID: 21383178 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Despite the success of protein farnesyltransferase inhibitors (FTIs) in the treatment of certain malignancies, their mode of action is incompletely understood. Dissecting the molecular pathways affected by FTIs is important, particularly because this group of drugs is now being tested for the treatment of Hutchinson-Gilford progeria syndrome. In the current study, we show that FTI treatment causes a centrosome separation defect, leading to the formation of donut-shaped nuclei in nontransformed cell lines, tumor cell lines, and tissues of FTI-treated mice. Donut-shaped nuclei arise during chromatin decondensation in late mitosis; subsequently, cells with donut-shaped nuclei exhibit defects in karyokinesis, develop aneuploidy, and are often binucleated. Binucleated cells proliferate slowly. We identified lamin B1 and proteasome-mediated degradation of pericentrin as critical components in FTI-induced "donut formation" and binucleation. Reducing pericentrin expression or ectopic expression of nonfarnesylated lamin B1 was sufficient to elicit donut formation and binucleated cells, whereas blocking proteasomal degradation eliminated FTI-induced donut formation. Our studies have uncovered an important role of FTIs on centrosome separation and define pericentrin as a (indirect) target of FTIs affecting centrosome position and bipolar spindle formation, likely explaining some of the anticancer effects of these drugs. |
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Authors:
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Valerie L R M Verstraeten; Lana A Peckham; Michelle Olive; Brian C Capell; Francis S Collins; Elizabeth G Nabel; Stephen G Young; Loren G Fong; Jan Lammerding |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-03-07 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-23 Completed Date: 2011-05-26 Revised Date: 2012-04-26 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 4997-5002 Citation Subset: IM |
Affiliation:
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Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens / biosynthesis, genetics Antineoplastic Agents / pharmacology* Cell Nucleus* / genetics, metabolism, pathology Centrosome* / metabolism, pathology Hep G2 Cells Humans Lamin Type B / biosynthesis, genetics Mice Mice, Transgenic Mitosis / drug effects*, genetics Mitotic Spindle Apparatus* / genetics, metabolism, pathology Progeria / genetics, metabolism, pathology Protein Prenylation / drug effects*, genetics |
| Grant Support | |
ID/Acronym/Agency:
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AG035626/AG/NIA NIH HHS; HL082792/HL/NHLBI NIH HHS; HL086683/HL/NHLBI NIH HHS; HL089781/HL/NHLBI NIH HHS; NS059348/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens; 0/Antineoplastic Agents; 0/Lamin Type B; 0/lamin B1; 0/pericentrin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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