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Antiapoptotic effect of c-fes protooncogene during granulocytic differentiation
S Ferrari1, R Manfredini, E Tagliafico
1Institute of Biological Chemistry, University of Modena, Italy.
Abstract:
The c-fes protooncogene is expressed at high levels in the terminal stages of granulocytic differentiation. Its product, p92c-fes, exhibits a tyrosine-kinase activity and is involved in the cellular response to GM-CSF, but its role is not yet clarified. To study this problem, the c-fes protooncogene expression has been inhibited in HL60 cells and in fresh leukemic blast cells of Acute Promyelocytic Leukemia (APL) induced to differentiate with All-Trans-Retinoic Acid (ATRA). Inhibition of c-fes function was obtained by treatment of the cells with a specific antisense oligomer complementary to the 5' region of the c-fes mRNA. It was observed that the cells, rather then differentiate to granulocytes, underwent premature cell death showing the morphological and molecular characteristics of apoptosis. Superimposable results are obtained on blast cells from APL. It is possible to conclude that the loss of cell viability that occurs during the in vitro differentiation of myeloid cells, after the complete inhibition of c-fes expression and treatment with ATRA, is due to activation of programmed cell death rather than an accelerated differentiation. Our data suggest that the c-fes product is essential for the survival of myeloid cells during differentiation.
Insights
Inhibition of the c-FES protooncogene in myeloid cells undergoing differentiation triggers apoptosis, not accelerated maturation. This suggests c-FES is crucial for myeloid cell survival during differentiation.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The c-FES protooncogene and its product p92c-FES, a tyrosine kinase, are highly expressed during granulocytic differentiation.
- p92c-FES is implicated in cellular responses to GM-CSF, but its precise role in myeloid differentiation remains unclear.
Purpose of the Study:
- To investigate the role of c-FES in myeloid cell differentiation and survival.
- To determine if c-FES inhibition affects differentiation or induces cell death.
Main Methods:
- Inhibition of c-FES protooncogene expression in HL60 cells and APL blast cells using a specific antisense oligomer.
- Induction of differentiation using All-Trans-Retinoic Acid (ATRA).
- Analysis of cell morphology and molecular markers to assess differentiation and apoptosis.
Main Results:
- Inhibition of c-FES led to premature cell death with characteristics of apoptosis, rather than granulocytic differentiation.
- Similar results were observed in both HL60 cells and primary APL blast cells.
- Loss of cell viability was attributed to apoptosis activation.
Conclusions:
- The c-FES product is essential for the survival of myeloid cells during differentiation.
- Inhibition of c-FES triggers programmed cell death (apoptosis) in differentiating myeloid cells.
- c-FES plays a critical role in preventing apoptosis during myeloid cell maturation.