title: Molecular mechanisms linking geranylgeranyl diphosphate synthase to cell survival and proliferation.
abstract: Geranylgeranyl diphosphate is a 20-carbon isoprenoid phospholipid whose lipid moiety can be post-translationally incorporated into proteins to promote membrane association. The process of geranylgeranylation has been implicated in anti-proliferative effects of clinical agents that inhibit enzymes of the mevalonate pathway (i.e. statins and nitrogenous bisphosphonates) as well as experimental agents that deplete geranylgeranyl diphosphate. Inhibitors of geranylgeranyl diphosphate synthase are an attractive way to block geranylgeranylation because they possess a calcium-chelating substructure to allow localization to bone and take advantage of a unique position of the enzyme within the biosynthetic pathway. Here, we describe recent advances in geranylgeranyl diphosphate synthase expression and inhibitor development with a particular focus on the molecular mechanisms that link geranylgeranyl diphosphate to cell proliferation via geranylgeranylated small GTPases.
authors.affiliation: a Department of Pharmaceutical Sciences , University of Connecticut , Storrs , CT , USA.
authors.forename: Sherry S
authors.initials: SS
authors.lastname: Agabiti
authors.affiliation: a Department of Pharmaceutical Sciences , University of Connecticut , Storrs , CT , USA.
authors.forename: Yilan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: a Department of Pharmaceutical Sciences , University of Connecticut , Storrs , CT , USA.|b Institute for Systems Genomics, University of Connecticut , Storrs , CT , USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wiemer
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000378:metabolism*; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D020559:Monomeric GTP-Binding Proteins; D008798:Mevalonic Acid
keywords: Bisphosphonates; GGDPS; Rac; Ras; Rho; small GTPase