Document Detail


Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24.
MedLine Citation:
PMID:  22448028     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Related Documents :
16608858 - Phospholipase d1 regulates cell migration in a lipase activity-independent manner.
17597278 - Apoptosis of hela cells induced by extract from cremanthodium humile.
18223668 - Comparative study on transduction and toxicity of protein transduction domains.
851398 - Vaccinia virus cytotoxin.
10746658 - Localization of leptin receptor-like immunoreactivity in the corticotropes, somatotrope...
8306528 - Hepatocyte growth factor stimulates invasion across reconstituted basement membranes by...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-23
Journal Detail:
Title:  Journal of lipid research     Volume:  53     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-10     Completed Date:  2012-09-07     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1176-82     Citation Subset:  IM    
Affiliation:
Department of Medicine and University of California, Los Angeles, CA 90095, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alkyl and Aryl Transferases / 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:
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:
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
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Innovative trial designs are practical solutions for improving the treatment of tuberculosis.
Next Document:  Role of leptin in the pancreatic beta-cell: effects and signalling pathways.