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PPARgamma induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A
S Altiok1, M Xu, B M Spiegelman
1Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
PPAR gamma is an adipose-selective nuclear hormone receptor that plays a key role in the control of adipocyte differentiation. Previous studies indicated that activation of ectopically expressed PPAR gamma induces differentiation when cells have ceased growth because of confluence. We show here that ligand activation of PPAR gamma is sufficient to induce growth arrest in fibroblasts and SV40 large T-antigen transformed, adipogenic HIB1B cells. Cell cycle withdrawal is accompanied by a decrease in the DNA-binding and transcriptional activity of the E2F/DP complex, which is attributable to an increase in the phosphorylation of these proteins, especially DP-1. This effect is a consequence of decreased expression of the catalytic subunit of the serine-threonine phosphatase PP2A. These data suggest an important role for PP2A in the control of E2F/DP activity and a new mode of cell cycle control in differentiation.
Insights
Ligand activation of PPAR gamma induces cell growth arrest by decreasing PP2A expression, impacting E2F/DP activity. This reveals a new mechanism controlling cell cycle during differentiation.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Peroxisome proliferator-activated receptor gamma (PPAR gamma) is crucial for adipocyte differentiation.
- Previous research showed PPAR gamma activation promotes differentiation in growth-arrested cells.
Purpose of the Study:
- To investigate the role of PPAR gamma in cell cycle regulation beyond differentiation.
- To elucidate the molecular mechanisms by which PPAR gamma influences cell growth.
Main Methods:
- Utilized fibroblasts and HIB1B cells (adipogenic, SV40 T-antigen transformed).
- Assessed cell growth arrest upon PPAR gamma ligand activation.
- Analyzed DNA-binding and transcriptional activity of E2F/DP complex.
- Measured protein phosphorylation (DP-1) and PP2A expression.
Main Results:
- PPAR gamma ligand activation induced growth arrest in tested cell types.
- Cell cycle withdrawal correlated with reduced E2F/DP DNA-binding and transcriptional activity.
- Increased phosphorylation of E2F/DP proteins, particularly DP-1, was observed.
- Decreased expression of the PP2A catalytic subunit was identified as the cause.
Conclusions:
- PPAR gamma activation directly induces cell growth arrest, independent of differentiation.
- PP2A plays a significant role in regulating E2F/DP activity.
- This study uncovers a novel pathway for cell cycle control mediated by PPAR gamma and PP2A during differentiation.