Atypical transcriptional regulators and cofactors of PPARgamma.

Regulation of peroxisome proliferator-activated receptor gamma (PPARgamma) activity is the result of several events. The first control level is the regulation of the expression of PPARgamma. Examples of this regulation, during adipogenesis, is the transactivation of the PPARgamma promoter by transcription factors of the classical pathway, such as C/EBPs or ADD1/SREBP1, but also newly identified factors, such as E2Fs. When preadipocytes re-enter the cell cycle, PPARgamma expression is induced coincident with an increase in DNA synthesis, suggesting the involvement of the E2F family of cell cycle regulators. E2F1 induces PPARgamma transcription during clonal expansion, whereas E2F4 represses PPARgamma expression during terminal adipocyte differentiation. Hence, E2Fs represent the link between proliferative signaling pathways, triggering clonal expansion, and terminal adipocyte differentiation through regulation of PPARgamma expression. A second regulatory level of PPARgamma action is interaction with cofactors. We will focus our attention on the atypical PPARgamma modulators. We have described an interaction between PPARgamma and the retinoblastoma protein, RB, which is both dependent upon ligand binding by PPARgamma and upon the phosphorylation status of RB. The interaction between PPARgamma and RB decreases the transcriptional activity of PPARgamma through recruitment of the histone deacetylase HDAC3. Inhibition of HDAC activity consequently results in a strong activation of PPARgamma.