PPARgamma induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A.
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.
Altiok
S
S
Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Xu
M
M
Spiegelman
B M
BM
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D008024:Ligands; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D056465:Retinoblastoma-Binding Protein 1; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D056465:Retinoblastoma-Binding Protein 1; C493736:Tfdp1 protein, mouse; D013844:Thiazoles; D045162:Thiazolidinediones; D050680:Transcription Factor DP1; D014157:Transcription Factors; D010749:Phosphoprotein Phosphatases; D000077205:Pioglitazone