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Interaction Between Mevalonate Pathway and Retinoic Acid-Induced Differentiation.

Gueddari-Pouzols N, Duriez P, Chomienne C, Trussardi A, Jardillier JC - J. Biomed. Biotechnol. (2001)

Bottom Line: The supply of an excess of cholesterol (up to 80 &mgr;g/ml of LDL) leads to a significant decrease of cell differentiation by ATRA from 78% +/-0.1 to 54% +/-2.8.A concomitant decrease of cell growth (51% +/- 6.4) was observed.The pretreatment of cells by the geranylgeranyltransferase inhibitor (GGTI-298) has no effect on the cell differentiation process.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
All trans retinoic acid (ATRA) is a potent inducer of differentiation of HL-60 cell line. The pretreatment of the cells by compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, during 24 hours, enhances the ATRA-induced cell differentiation. At 50 nM, the percentage of cell differentiation is 34.9% +/- 2 and 73% +/- 2.96 in the control and compactin-treated cells, respectively. The removal of compactin boosts the level of HMG-CoA reductase and therefore the biosynthesis of sterol and nonsterol isoprenoid compounds. The participation of sterol and nonsterol pathway was then investigated. The supply of an excess of cholesterol (up to 80 &mgr;g/ml of LDL) leads to a significant decrease of cell differentiation by ATRA from 78% +/-0.1 to 54% +/-2.8. A concomitant decrease of cell growth (51% +/- 6.4) was observed. The pretreatment of cells by the geranylgeranyltransferase inhibitor (GGTI-298) has no effect on the cell differentiation process. By contrast, the farnesyltransferase inhibitors (FTI-II and FTI-277) completely abolish theATRA-induced differentiation, thus confirming the involvement of farnesylated proteins in the differentiation mechanism.

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Inhibition of H-ras, N-ras, and K-ras prenylation by FTI-II, FTI-277, and GGTI-298 HL-60 cells were treated with 5 or 10 μM of FTI-II or 10 μM of FTI-277 or GGTI-298 for 24 hours. Cell lysates were analyzed by Western blotting with either a H-ras monoclonal antibody or a N-ras polyclonal antibody or a K-ras monoclonal antibody. Arrows, unprenylated ras bands.
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Figure 5: Inhibition of H-ras, N-ras, and K-ras prenylation by FTI-II, FTI-277, and GGTI-298 HL-60 cells were treated with 5 or 10 μM of FTI-II or 10 μM of FTI-277 or GGTI-298 for 24 hours. Cell lysates were analyzed by Western blotting with either a H-ras monoclonal antibody or a N-ras polyclonal antibody or a K-ras monoclonal antibody. Arrows, unprenylated ras bands.

Mentions: When the cells were preincubated in the presence of 10 μM of GGTI-298 during 24 hours, then treated by ATRA during 3 days, no significant result was observed compared with control cells whereas, at the same concentration (10 μM), FTI-II and FTI-277 decrease ATRA-induced differentiation of the cells (Figure 4). The prenylation of H-ras, K-ras, and N-ras in the cells is effectivelyinhibited under the conditions tested (Figure 5). This result suggested that farnesylated proteins, such as H-ras, K-ras, and N-ras, could be implied in the mechanism of cell differentiation by ATRA.


Interaction Between Mevalonate Pathway and Retinoic Acid-Induced Differentiation.

Gueddari-Pouzols N, Duriez P, Chomienne C, Trussardi A, Jardillier JC - J. Biomed. Biotechnol. (2001)

Inhibition of H-ras, N-ras, and K-ras prenylation by FTI-II, FTI-277, and GGTI-298 HL-60 cells were treated with 5 or 10 μM of FTI-II or 10 μM of FTI-277 or GGTI-298 for 24 hours. Cell lysates were analyzed by Western blotting with either a H-ras monoclonal antibody or a N-ras polyclonal antibody or a K-ras monoclonal antibody. Arrows, unprenylated ras bands.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC129055&req=5

Figure 5: Inhibition of H-ras, N-ras, and K-ras prenylation by FTI-II, FTI-277, and GGTI-298 HL-60 cells were treated with 5 or 10 μM of FTI-II or 10 μM of FTI-277 or GGTI-298 for 24 hours. Cell lysates were analyzed by Western blotting with either a H-ras monoclonal antibody or a N-ras polyclonal antibody or a K-ras monoclonal antibody. Arrows, unprenylated ras bands.
Mentions: When the cells were preincubated in the presence of 10 μM of GGTI-298 during 24 hours, then treated by ATRA during 3 days, no significant result was observed compared with control cells whereas, at the same concentration (10 μM), FTI-II and FTI-277 decrease ATRA-induced differentiation of the cells (Figure 4). The prenylation of H-ras, K-ras, and N-ras in the cells is effectivelyinhibited under the conditions tested (Figure 5). This result suggested that farnesylated proteins, such as H-ras, K-ras, and N-ras, could be implied in the mechanism of cell differentiation by ATRA.

Bottom Line: The supply of an excess of cholesterol (up to 80 &mgr;g/ml of LDL) leads to a significant decrease of cell differentiation by ATRA from 78% +/-0.1 to 54% +/-2.8.A concomitant decrease of cell growth (51% +/- 6.4) was observed.The pretreatment of cells by the geranylgeranyltransferase inhibitor (GGTI-298) has no effect on the cell differentiation process.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
All trans retinoic acid (ATRA) is a potent inducer of differentiation of HL-60 cell line. The pretreatment of the cells by compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG) CoA reductase, during 24 hours, enhances the ATRA-induced cell differentiation. At 50 nM, the percentage of cell differentiation is 34.9% +/- 2 and 73% +/- 2.96 in the control and compactin-treated cells, respectively. The removal of compactin boosts the level of HMG-CoA reductase and therefore the biosynthesis of sterol and nonsterol isoprenoid compounds. The participation of sterol and nonsterol pathway was then investigated. The supply of an excess of cholesterol (up to 80 &mgr;g/ml of LDL) leads to a significant decrease of cell differentiation by ATRA from 78% +/-0.1 to 54% +/-2.8. A concomitant decrease of cell growth (51% +/- 6.4) was observed. The pretreatment of cells by the geranylgeranyltransferase inhibitor (GGTI-298) has no effect on the cell differentiation process. By contrast, the farnesyltransferase inhibitors (FTI-II and FTI-277) completely abolish theATRA-induced differentiation, thus confirming the involvement of farnesylated proteins in the differentiation mechanism.

No MeSH data available.


Related in: MedlinePlus