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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.

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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.


Effect of farnesyltransferase inhibitors on differentiation of HL-60 cells by ATRA. HL-60 cells were pretreated with increasing concentrations of FTI-II (•) or FTI-277 (∘). After 24 hours, The ATRA (1 μM) was added to culture medium. Cell differentiation was determined at day 4.
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Figure 3: Effect of farnesyltransferase inhibitors on differentiation of HL-60 cells by ATRA. HL-60 cells were pretreated with increasing concentrations of FTI-II (•) or FTI-277 (∘). After 24 hours, The ATRA (1 μM) was added to culture medium. Cell differentiation was determined at day 4.

Mentions: The cells were preincubated in the presence of the farsnesyltransferase inhibitor II or farnesyltransferase inhibitor FTI-277 during 24 hours, then treated by ATRA during 3 days (Figure 3). A strong decrease of ATRA-induced differentiation was observed with increasing concentrations of both inhibitors. FTI-277 was a more potentinhibitor compared with FTI-II (Figure 3). Indeed, the differentiating activity by ATRA was totally abolished at 25 μM of FTI-277 (Figure 3) and 40 μM of FTI-II (data not shown). These results confirmed the involvementof the nonsterol mevalonate pathway in cell differentiation.


Interaction Between Mevalonate Pathway and Retinoic Acid-Induced Differentiation.

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

Effect of farnesyltransferase inhibitors on differentiation of HL-60 cells by ATRA. HL-60 cells were pretreated with increasing concentrations of FTI-II (•) or FTI-277 (∘). After 24 hours, The ATRA (1 μM) was added to culture medium. Cell differentiation was determined at day 4.
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Related In: Results  -  Collection

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Figure 3: Effect of farnesyltransferase inhibitors on differentiation of HL-60 cells by ATRA. HL-60 cells were pretreated with increasing concentrations of FTI-II (•) or FTI-277 (∘). After 24 hours, The ATRA (1 μM) was added to culture medium. Cell differentiation was determined at day 4.
Mentions: The cells were preincubated in the presence of the farsnesyltransferase inhibitor II or farnesyltransferase inhibitor FTI-277 during 24 hours, then treated by ATRA during 3 days (Figure 3). A strong decrease of ATRA-induced differentiation was observed with increasing concentrations of both inhibitors. FTI-277 was a more potentinhibitor compared with FTI-II (Figure 3). Indeed, the differentiating activity by ATRA was totally abolished at 25 μM of FTI-277 (Figure 3) and 40 μM of FTI-II (data not shown). These results confirmed the involvementof the nonsterol mevalonate pathway in cell differentiation.

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.