Notch-1 Controls the Expression of Fatty Acid-activated Transcription Factors and Is Required for Adipogenesis*
- Carmen Garcés‡,
- M. J. Ruiz-Hidalgo‡,
- Jaime Font de Mora§,
- Crystal Park‡,
- Lucio Miele‡,
- Julia Goldstein‡,
- Ezio Bonvini‡,
- Almudena Porrás§ and
- Jorge Laborda‡¶
- From the ‡Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Bethesda, Maryland 20852 and the §Laboratory of Cellular and Molecular Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892
Abstract
Notch, a transmembrane receptor member of the homeotic epidermal growth factor-like family of proteins, participates in cell-to-cell signaling to control cell fate during development. Activated Notch-1 constructs lacking the extracellular region prevent differentiation of several mammalian cells in vitro. This effect, however, bypasses the normal mechanisms of cell-to-cell interactions in which Notch-1 participates. We investigated the role of Notch-1 in the hormone-induced adipocyte differentiation of 3T3-L1 fibroblasts, a paradigmatic model of adipogenesis that requires cell-to-cell contact. Unlike other differentiation models, Notch-1 expression and function were necessary conditions for adipogenesis. Impaired Notch-1 expression by antisenseNotch-1 constructs prevented adipocyte differentiation. Strategies aimed at blocking putative Notch/ligand interactions also blocked adipogenesis, implicating Notch as a critical molecule in cell-to-cell signaling necessary for differentiation. Inhibition of Notch-1 expression or function decreased the expression of peroxisomal proliferator-activated receptors δ and γ, transcription factors that control adipocyte differentiation and that are up-regulated at cell confluence. These results implicate Notch in the commitment of 3T3-L1 cells to undergo adipogenesis by controlling the expression of the principal regulators of this process.
Footnotes
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↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ To whom correspondence should be addressed: Lab. of Immunobiology, HFM 564, Div. of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Bldg. 29B/3NN04, 1401 Rockville Pike, Rockville, MD 20852. Tel.: 301-827-0709; Fax: 301-827-0852.
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↵1 The abbreviations used are: EGF, epidermal growth factor; C/EBP, CAATT enhancer-binding protein; PPAR, peroxisomal proliferator-activated receptor; RT-PCR, reverse transcription-polymerase chain reaction.
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- Received July 14, 1997.
- Revision received August 26, 1997.
