Isoprenoid pyrophosphate analogues regulate expression of ras-related proteins

Sarah A Holstein, Christine L. Wohlford-Lenane, David F. Wiemer, Raymond J. Hohl

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4384-4391
Number of pages8
JournalBiochemistry
Volume42
Issue number15
DOIs
StatePublished - Apr 22 2003

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ras Proteins
Terpenes
Diphosphates
Mevalonic Acid
Proteins
Up-Regulation
Transferases
Geranylgeranyl-Diphosphate Geranylgeranyltransferase
Phosphorous Acids
Molecules
Protein Prenylation
Prenylation
Retinoids
Tretinoin
Metabolites
diphosphoric acid
Functional groups
Restoration
Head
farnesyl pyrophosphate

ASJC Scopus subject areas

  • Biochemistry

Cite this

Isoprenoid pyrophosphate analogues regulate expression of ras-related proteins. / Holstein, Sarah A; Wohlford-Lenane, Christine L.; Wiemer, David F.; Hohl, Raymond J.

In: Biochemistry, Vol. 42, No. 15, 22.04.2003, p. 4384-4391.

Research output: Contribution to journalArticle

Holstein, Sarah A ; Wohlford-Lenane, Christine L. ; Wiemer, David F. ; Hohl, Raymond J. / Isoprenoid pyrophosphate analogues regulate expression of ras-related proteins. In: Biochemistry. 2003 ; Vol. 42, No. 15. pp. 4384-4391.
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