Journal article
Isoprenoid pyrophosphate analogues regulate expression of Ras-related proteins
Biochemistry (Easton), Vol.42(15), pp.4384-4391
04/22/2003
DOI: 10.1021/bi027227m
PMID: 12693933
Abstract
The isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are synthetic precursors for numerous molecules essential for cellular function as well as substrates in isoprenylation reactions. We have previously demonstrated that depletion of mevalonate results in the upregulation of Ras-related proteins which can be prevented by FPP or GGPP, independent of restoration of protein isoprenylation. To better define the regulatory properties of isoprenoid pyrophosphates, we have investigated the abilities of isoprenoid analogues to regulate the expression of the Ras-related proteins. Farnesyl phosphonic acids potentiate the upregulation of these proteins induced by mevalonate depletion independent of inhibitory activity against farnesyl protein transferase, geranylgeranyl protein transferase I, FPP synthase, or GGPP synthase. The potentiation of RhoB upregulation is at both the mRNA and protein level. The ability of these analogues to serve as functional antagonists of the isoprenoid pyrophosphates is dependent on the nature of the functional group at the head of the molecule, the charge of the molecule, and the length of the isoprenoid chain. Metabolites and additional analogues of isoprenoid pyrophosphates were found to possess agonist properties relative to FPP and GGPP. Interestingly, the structurally related retinoids all-trans-retinoic acid and 9-cis-retinoic acid also display slight agonist properties. These studies provide evidence for direct roles of FPP and GGPP in regulating transcriptional and post-transcriptional events.
Details
- Title: Subtitle
- Isoprenoid pyrophosphate analogues regulate expression of Ras-related proteins
- Creators
- Sarah A Holstein - Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242, USAChristine L Wohlford-LenaneDavid F WiemerRaymond J Hohl
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.42(15), pp.4384-4391
- Publisher
- United States
- DOI
- 10.1021/bi027227m
- PMID
- 12693933
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Language
- English
- Date published
- 04/22/2003
- Academic Unit
- Pulmonary Medicine; Stead Family Department of Pediatrics; Neuroscience and Pharmacology; Chemistry; Internal Medicine
- Record Identifier
- 9983986086302771
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