| Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24. | |
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MedLine Citation:
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PMID: 22448028 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Protein farnesyltransferase (FTase) inhibitors, generally called "FTIs," block the farnesylation of prelamin A, inhibiting the biogenesis of mature lamin A and leading to an accumulation of prelamin A within cells. A recent report found that a GGTI, an inhibitor of protein geranylgeranyltransferase-I (GGTase-I), caused an exaggerated accumulation of prelamin A in the presence of low amounts of an FTI. This finding was interpreted as indicating that prelamin A can be alternately prenylated by GGTase-I and that inhibiting both protein prenyltransferases leads to more prelamin A accumulation than blocking FTase alone. Here, we tested an alternative hypothesis-GGTIs are not specific for GGTase-I, and they lead to prelamin A accumulation by inhibiting ZMPSTE24 (a zinc metalloprotease that converts farnesyl-prelamin A to mature lamin A). In our studies, commonly used GGTIs caused prelamin A accumulation in human fibroblasts, but the prelamin A in GGTI-treated cells exhibited a more rapid electrophoretic mobility than prelamin A from FTI-treated cells. The latter finding suggested that the prelamin A in GGTI-treated cells might be farnesylated (which would be consistent with the notion that GGTIs inhibit ZMPSTE24). Indeed, metabolic labeling studies revealed that the prelamin A in GGTI-treated fibroblasts is farnesylated. Moreover, biochemical assays of ZMPSTE24 activity showed that ZMPSTE24 is potently inhibited by a GGTI. Our studies show that GGTIs inhibit ZMPSTE24, leading to an accumulation of farnesyl-prelamin A. Thus, caution is required when interpreting the effects of GGTIs on prelamin A processing. |
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Authors:
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Sandy Y Chang; Sarah E Hudon-Miller; Shao H Yang; Hea-Jin Jung; John M Lee; Emily Farber; Thangaiah Subramanian; Douglas A Andres; H Peter Spielmann; Christine A Hrycyna; Stephen G Young; Loren G Fong |
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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: 2012-03-23 |
Journal Detail:
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Title: Journal of lipid research Volume: 53 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-05-10 Completed Date: 2012-09-07 Revised Date: 2013-04-02 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 1176-82 Citation Subset: IM |
Affiliation:
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Department of Medicine and University of California, Los Angeles, CA 90095, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alkyl and Aryl Transferases
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antagonists & inhibitors* Animals Fibroblasts / drug effects, metabolism Humans Membrane Proteins / antagonists & inhibitors* Metalloendopeptidases / antagonists & inhibitors* Mice Nuclear Proteins / metabolism* Peptidomimetics / pharmacology* Protease Inhibitors / pharmacology* Protein Precursors / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AG-035626/AG/NIA NIH HHS; GM-66152/GM/NIGMS NIH HHS; HL-089781/HL/NHLBI NIH HHS; HL-76839/HL/NHLBI NIH HHS; HL-86683/HL/NHLBI NIH HHS; R01 AG035626/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Membrane Proteins; 0/Nuclear Proteins; 0/Peptidomimetics; 0/Protease Inhibitors; 0/Protein Precursors; 0/prelamin A; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.-/geranylgeranyltransferase type-I; EC 3.4.24.-/Metalloendopeptidases; EC 3.4.24.84/ZMPSTE24 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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