Geranylgeranylated proteins are involved in the regulation of myeloma cell growth.
OBJECTIVE
Prenylation is essential for membrane localization and participation of proteins in various signaling pathways. This study examined the role of farnesylated and geranylgeranylated proteins in the regulation of myeloma cell proliferation.


METHODS
Antiproliferative and apoptotic effects of various modulators of farnesylated and geranylgeranylated proteins were investigated in myeloma cells.


RESULTS
Depletion of geranylgeranylpyrophosphate inhibited myeloma cell proliferation through accumulation of cells in G(1) phase of the cell cycle and loss of cells in S phase. In contrast, depletion of farnesylpyrophosphate had no or only minor effects. Furthermore, inhibition of geranylgeranyl transferase I activity was more effective in reducing myeloma cell growth when compared with inhibition of farnesyl transferase activity. This indicates that protein geranylgeranylation is important for myeloma cell proliferation and cell cycle progression through G(1). Geranylgeranylated target proteins involved in the control of proliferation include GTPases, such as Rac-1, Cdc42, and RhoA. Inhibition of Rho, Rac, and Cdc42 GTPases by toxin B reduced proliferation, without affecting cell viability, whereas specific inhibition of Rho GTPases by C3 exoenzyme was without effect. This suggests a role for Rac and/or Cdc42 GTPases in myeloma cell growth. Rac-1 activity was found in all myeloma cell lines and was suppressed by the depletion of intracellular pools of geranylgeranylpyrophosphate, whereas interleukin-6 rapidly induced Rac-1 activation. Furthermore, dominant-negative Tat-Rac-1 reduced myeloma cell proliferation, whereas constitutively active Tat-Rac-1 enhanced proliferation.


CONCLUSIONS
These results indicate that protein geranylgeranylation is essential for myeloma cell proliferation and suggest that Rac-1 is a regulator of myeloma cell growth.
van de Donk
Niels W C J
NW
Department of Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
Lokhorst
Henk M
HM
Nijhuis
Evert H J
EH
Kamphuis
Marloes M J
MM
Bloem
Andries C
AC
D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D049109:Cell Proliferation; D051231:Farnesyltranstransferase; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017368:Protein Prenylation / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012717:Sesquiterpenes; D014407:Tumor Cells, Cultured; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D015850:Interleukin-6; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate