Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis.
Molecular mechanisms coupling growth arrest and cell differentiation were examined during adipogenesis. Data are presented that document a cascade expression of members of two independent families of cyclin-dependent kinase inhibitors that define distinct states of growth arrest during 3T3-L1 preadipocyte differentiation. Exit from the cell cycle into a pre-differentiation state of post-mitotic growth arrest was characterized by significant increases in p21 and p27. During onset of irreversible growth arrest associated with terminal differentiation, the level of p21 declined with a concomitant, dramatic increase in p18 and a sustained level of p27. The expression of p18 and p21, regulated at the level of protein and mRNA accumulation, was directly coupled to differentiation. Stable cell lines were engineered to express adipogenic transcription factors to examine the active role of trans-acting elements in regulating these cell cycle inhibitors. Ectopic expression of peroxisome proliferator-activated receptor (PPAR) gamma in non-precursor fibroblastic cell lines resulted in conversion to adipocytes and a coordinated increase in p18 and p21 mRNA and protein expression in a PPARgamma ligand-associated manner. These data demonstrate a role for PPARgamma in mediating the differentiation-dependent cascade expression of cyclin-dependent kinase inhibitors, thereby providing a molecular mechanism coupling growth arrest and adipocyte differentiation.
Morrison
R F
RF
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Farmer
S R
SR
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004791:Enzyme Inhibitors; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009687:Nuclear Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D018844:Cyclin-Dependent Kinases