TY - JOUR
T1 - Geranylgeraniol overcomes the block of cell proliferation by lovastatin in C6 glioma cells
AU - Crick, Dean C.
AU - Andres, Douglas A.
AU - Danesi, Romano
AU - Macchia, Marco
AU - Waechter, Charles J.
PY - 1998/6
Y1 - 1998/6
N2 - It is well documented that 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors prevent cultured mammalian cells from progressing through the cell cycle, suggesting a critical role for a mevalonate-derived product. Recently, it has been shown that free geranylgeraniol (GG-OH) and farnesol (F-OH) can be utilized by C6 glioma cells for protein isoprenylation. The ability of GG- OH and F-OH to restore protein geranylgeranylation or farnesylation selectively has enabled us to examine the possibility that mevalonate is essential for cell proliferation because it is a precursor of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, the isoprenyl donors involved in the post-translational modification of key regulatory proteins. In this study we report that GG-OH, as well as mevalonate, overcomes the arrest of cell proliferation of C6 glioma cells treated with lovastatin, as assessed by increased cell numbers and a stimulation in [3H]thymidine incorporation. The increase in cell number and [3H]thymidine incorporation were significantly lower when F-OH was added. Under these conditions [3H]mevalonate and [3H]GG-OH are actively incorporated into a set of isoprenylated proteins in the size range of small, GTP-binding proteins (19-27 kDa) and a polypeptide with the molecular size (46 kDa) of the smaller isoform of 2',3'-cyclic nucleotide 3'-phosphodiesterase. Analysis of the proteins metabolically labeled by [3H]mevalonate and [3H]GG-OH reveals the presence of labeled proteins containing geranylgeranylated cysteinyl residues. Consistent with geranylgeranylated proteins playing a critical role in the entry of C6 cells into the cell cycle, a (phosphonoacetamido)oxy derivative of GG-OH, a drag previously shown to interfere with protein geranylgeranylation, prevented the increase in cell number when mevalonate or GG-OH was added to lovastatin- treated cells. These results strongly suggest that geranylgeranylated proteins are essential for progression of C6 cells into the S phase of the cell cycle and provide the first evidence that the 'salvage' pathway for the utilization of the free isoprenols is physiologically significant in the CNS.
AB - It is well documented that 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors prevent cultured mammalian cells from progressing through the cell cycle, suggesting a critical role for a mevalonate-derived product. Recently, it has been shown that free geranylgeraniol (GG-OH) and farnesol (F-OH) can be utilized by C6 glioma cells for protein isoprenylation. The ability of GG- OH and F-OH to restore protein geranylgeranylation or farnesylation selectively has enabled us to examine the possibility that mevalonate is essential for cell proliferation because it is a precursor of farnesyl pyrophosphate or geranylgeranyl pyrophosphate, the isoprenyl donors involved in the post-translational modification of key regulatory proteins. In this study we report that GG-OH, as well as mevalonate, overcomes the arrest of cell proliferation of C6 glioma cells treated with lovastatin, as assessed by increased cell numbers and a stimulation in [3H]thymidine incorporation. The increase in cell number and [3H]thymidine incorporation were significantly lower when F-OH was added. Under these conditions [3H]mevalonate and [3H]GG-OH are actively incorporated into a set of isoprenylated proteins in the size range of small, GTP-binding proteins (19-27 kDa) and a polypeptide with the molecular size (46 kDa) of the smaller isoform of 2',3'-cyclic nucleotide 3'-phosphodiesterase. Analysis of the proteins metabolically labeled by [3H]mevalonate and [3H]GG-OH reveals the presence of labeled proteins containing geranylgeranylated cysteinyl residues. Consistent with geranylgeranylated proteins playing a critical role in the entry of C6 cells into the cell cycle, a (phosphonoacetamido)oxy derivative of GG-OH, a drag previously shown to interfere with protein geranylgeranylation, prevented the increase in cell number when mevalonate or GG-OH was added to lovastatin- treated cells. These results strongly suggest that geranylgeranylated proteins are essential for progression of C6 cells into the S phase of the cell cycle and provide the first evidence that the 'salvage' pathway for the utilization of the free isoprenols is physiologically significant in the CNS.
KW - Cell cycle
KW - Geranylgeraniol
KW - Geranylgeranyl pyrophosphate
KW - Lovastatin
KW - Protein isoprenylation
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UR - http://www.scopus.com/inward/citedby.url?scp=0031800322&partnerID=8YFLogxK
U2 - 10.1046/j.1471-4159.1998.70062397.x
DO - 10.1046/j.1471-4159.1998.70062397.x
M3 - Article
C2 - 9603204
AN - SCOPUS:0031800322
SN - 0022-3042
VL - 70
SP - 2397
EP - 2405
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 6
ER -