Severe hepatocellular disease in mice lacking one or both CaaX prenyltransferases

Yang, Shao Hua; Chang, Shoou‐Yuh; Tu, Yiping; Lawson, Gregory; Bergö, Martin O.; Fong, Loren G.; Young, Stephen G.

doi:10.1194/jlr.m021220

Cited by 16 publications

(19 citation statements)

References 40 publications

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“…5 ) ( 35 ). AlbCre + , labeled "GGTase KO") ( 37 ). Hepatocytes were isolated from these mice, and cell extracts were blotted with antibodies against lamin A/C and prelamin A. Wild-type hepatocytes treated with DMSO or an FTI (ABT-100) and Fntb -defi cient hepatocytes (labeled "FTase KO," prepared from the liver of an Fntb fl /fl AlbCre + mouse) were included as controls.…”

Section: Resultsmentioning

confidence: 99%

“…In the end, a definitive understanding of prelamin A alternate prenylation will require direct biochemical assays and genetic studies in which the CaaX prenyltransferases are inactivated with genetic rather than pharmacologic approaches. Some studies with tissue-specific knockout mice have already been reported ( 37,47 ), and they suggest that alternate prenylation of prelamin A, if it occurs in vivo, may not be particularly efficient.…”

Section: Discussionmentioning

confidence: 99%

“…The cells were seeded in collagen-coated plates and allowed to adhere for 4 h before preparing cell extracts. Quantitative RT-PCR studies ( 37 ) …”

Section: Growth Of Human Fi Broblasts and Inhibitors Of The Protein Pmentioning

confidence: 99%

“…AG is converted to anilinogeranyl diphosphate (AGPP) and used as a substrate by FTase. The incorporation of AG into prelamin A can be detected by Western blotting with an AG-specifi c monoclonal antibody (1:5000) ( 38 ) and an IRDye 680-labeled anti-mouse IgG (1:2500) (LI-COR) ( 23,37,39 ).…”

Section: Metabolic Labeling Of Farnesylated Proteins In Fi Broblastsmentioning

confidence: 99%

“…The IRdye-labeled antibodies were detected with an Odyssey infrared imaging scanner (LI-COR Biosciences), and the HRP-labeled antibodies were detected by Enhanced Chemiluminescence methods and exposure to X-ray fi lm. were isolated by collagenase digestion and differential centrifugation ( 37 ). The cells were seeded in collagen-coated plates and allowed to adhere for 4 h before preparing cell extracts.…”

Section: Growth Of Human Fi Broblasts and Inhibitors Of The Protein Pmentioning

confidence: 99%

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Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24

Chang

Hudon-Miller

Yang

et al. 2012

Journal of Lipid Research

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Prelamin A and other proteins containing a carboxylterminal CaaX motif undergo a series of posttranslational modifi cations, beginning with protein prenylation ( 1-4 ). First, a 15-carbon farnesyl or a 20-carbon geranylgeranyl lipid is added to the thiol group of the cysteine (the "C" of the CaaX motif) by a pair of protein prenyltransferases, protein farnesyltransferase (FTase) or protein geranylgeranyltransferase I (GGTase-I) ( 1, 2 ). Generally, the cysteine is geranylgeranylated if the "X" is a leucine or phenylalanine; otherwise, it is farnesylated ( 1, 2 ). Prelamin A terminates with -CSIM and is farnesylated ( 5-7 ). Next, the last three amino acids of the protein (i.e., the "aaX" of the CaaX motif) are clipped off by a prenylprotein-specifi c endoprotease ( 8 ). For most proteins, this step is carried out by RCE1 ( 8 ), but in the case of prelamin A, this step can be carried out by both zinc metalloprotease Ste24p ortholog (ZMPSTE24) and RCE1 ( 9, 10 ). Finally, the newly exposed isoprenylcysteine is methylated by ICMT ( 11-13 ). After these CaaX modifi cations are complete, prelamin A undergoes a second endoproteolytic processing step ( 14 ); the last 15 amino acids of the protein, including the farnesylcysteine methyl ester, are clipped off by ZMPSTE24, releasing mature lamin A ( 9, 15-18 ).Abstract 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 fi nding 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 specifi c for GGTase-I, and they lead to prelamin A accumulation by inhibiting ZMPSTE24 (a zinc metalloprotease that converts farnesylprelamin 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 fi nding 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 fi broblasts 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. Inhibitors of protein geranylgeranyltransferase-I lead toThis work was supported by National Institutes...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…The cells were seeded in collagen-coated plates and allowed to adhere for 4 h before preparing cell extracts. Quantitative RT-PCR studies ( 37 ) …”

Section: Growth Of Human Fi Broblasts and Inhibitors Of The Protein Pmentioning

confidence: 99%

Section: Metabolic Labeling Of Farnesylated Proteins In Fi Broblastsmentioning

confidence: 99%

Section: Growth Of Human Fi Broblasts and Inhibitors Of The Protein Pmentioning

confidence: 99%

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Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24

Chang

Hudon-Miller

Yang

et al. 2012

Journal of Lipid Research

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2013

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Regulation of protein prenylation

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Severe hepatocellular disease in mice lacking one or both CaaX prenyltransferases

Cited by 16 publications

References 40 publications

Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24

Inhibitors of protein geranylgeranyltransferase-I lead to prelamin A accumulation in cells by inhibiting ZMPSTE24

Recent Progress in Developing Small Molecule Inhibitors Designed to Interfere with Ras Membrane Association

Regulation of protein prenylation

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