Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes.
The process of adipogenesis involves a complex program of gene expression that includes down-regulation of the gene encoding Hes-1, a target of the Notch signaling pathway. To determine if Notch signaling affects adipogenesis, we exposed 3T3-L1 preadipocytes to the Notch ligand Jagged1 and found that differentiation was significantly reduced. This effect could be mimicked by constitutive expression of Hes-1. The block was associated with a complete loss of C/EBPalpha and peroxisome proliferator-activated receptor gamma (PPARgamma) induction and could be overcome by retroviral expression of either C/EBPalpha or PPARgamma2. Surprisingly, small interfering RNA (siRNA)-mediated reduction of Hes-1 mRNA in 3T3-L1 cells also inhibited differentiation, suggesting an additional, obligatory role for Hes-1 in adipogenesis. This role may be related to our observation that both Notch signaling and Hes-1 down-regulate transcription of the gene encoding DLK/Pref-1, a protein known to inhibit differentiation of 3T3-L1 cells. The results presented in this study establish a new target downstream of the Notch-Hes-1 pathway and suggest a dual role for Hes-1 in adipocyte development.
Ross
David A
DA
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145, USA.
Rao
Prakash K
PK
Kadesch
Tom
T
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000502:physiology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011506:Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C512925:Dlk1 protein, mouse; C489734:Hes1 protein, mouse; C000606274:Jag1 protein, mouse