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Inhibition of the terminal stages of adipocyte differentiation by cMyc
V J Heath1, D A Gillespie, D H Crouch
1Wolfson Laboratory for Molecular Pathology, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, United Kingdom.
Abstract:
The nuclear oncoprotein Myc is a pivotal regulator of several important biological processes, including cellular proliferation, differentiation, and apoptosis. Deregulated Myc expression is incompatible with terminal differentiation in a variety of cell types, including adipocytes. To understand how Myc inhibits adipogenesis, we analyzed the effect of Myc on the expression of genes characteristic of distinct phases of the hormonally induced adipogenic differentiation program in 3T3-L1 preadipocytes. We show that the early regulators, C/EBPbeta and C/EBPdelta, are induced normally in response to hormone in 3T3-L1 preadipocytes constitutively expressing Myc, but that expression of the downstream regulators, C/EBPalpha and PPARgamma2, and later markers of differentiation is suppressed. These data demonstrate that Myc specifically inhibits the terminal stages of the adipogenic program and suggest that Myc may act by blocking C/EBPbeta- and C/EBPdelta-directed activation of C/EBPalpha and PPARgamma2 expression, although the precise molecular mechanism is not understood. Surprisingly, a serum component(s) could override the Myc-induced differentiation block, suggesting that the ability of a cell to undergo terminal differentiation is governed by the action of both positive and negative factors. Since differentiation and proliferation are mutually exclusive events, this has important implications since it may be possible to force malignant cells along a differentiation pathway, thereby curbing their proliferative potential.
Insights
The oncoprotein Myc blocks terminal adipocyte differentiation by inhibiting key gene expression. However, serum factors can overcome this block, suggesting a balance of factors controls differentiation.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The nuclear oncoprotein Myc regulates cell proliferation, differentiation, and apoptosis.
- Deregulated Myc expression prevents terminal differentiation in various cell types, including adipocytes.
Purpose of the Study:
- To investigate how Myc inhibits adipogenesis (fat cell formation).
- To analyze Myc's effect on gene expression during adipogenic differentiation in 3T3-L1 preadipocytes.
Main Methods:
- Constitutive Myc expression in 3T3-L1 preadipocytes.
- Analysis of gene expression during hormonally induced adipogenic differentiation.
- Assessment of early and downstream regulators of adipogenesis.
Main Results:
- Early adipogenic regulators (C/EBPbeta, C/EBPdelta) were normally induced by Myc.
- Downstream regulators (C/EBPalpha, PPARgamma2) and later differentiation markers were suppressed by Myc.
- A serum component could override Myc-induced differentiation block.
Conclusions:
- Myc specifically inhibits the terminal stages of adipogenesis.
- Myc may block the activation of C/EBPalpha and PPARgamma2 by C/EBPbeta and C/EBPdelta.
- Cellular differentiation is regulated by both positive and negative factors, with implications for controlling malignant cell proliferation.