Isoprenoids influence expression of Ras and Ras-related proteins.
Mevalonate depletion by inhibition of hydroxymethylglutaryl coenzyme A reductase impairs post-translational processing of Ras and Ras-related proteins. We have previously shown that this mevalonate depletion also leads to the upregulation of Ras, Rap1a, RhoA, and RhoB. This upregulation may result from global inhibition of isoprenylation or depletion of key regulatory isoprenoid species. Studies utilizing specific isoprenoid pyrophosphates in mevalonate-depleted cells reveal that farnesyl pyrophosphate (FPP) restores Ras processing and prevents RhoB upregulation while geranylgeranyl pyrophosphate (GGPP) restores Rap1a processing and prevents RhoA and RhoB upregulation. Either FPP or GGPP completely prevents lovastatin-induced upregulation of RhoB mRNA. Inhibition of FPP or squalene synthase allowed for the further identification of the putative regulatory species. Studies involving the specific isoprenyl transferase inhibitors FTI-277 and GGTI-286 demonstrate that selective inhibition of protein isoprenylation does not mimic lovastatin's ability to increase Ras and RhoA synthesis, decrease Ras and RhoA degradation, increase RhoB mRNA, or increase total levels of Ras, Rap1a, RhoA, and RhoB. In aggregate, these findings reveal a novel role and mechanism for isoprenoids to influence levels of Ras and Ras-related proteins.
Holstein
Sarah A
SA
Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242, USA.
Wohlford-Lenane
Christine L
CL
Hohl
Raymond J
RJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D020014:K562 Cells; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism* / Q000494:pharmacology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012717:Sesquiterpenes; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C096856:FTI 277; C437105:GGTI 286; D011106:Polyisoprenyl Phosphates; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D003513:Cycloheximide; D008148:Lovastatin; D008715:Methionine; D013186:Farnesyl-Diphosphate Farnesyltransferase; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein; D007930:Leucine; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid