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- W2885483780 endingPage "14757" @default.
- W2885483780 startingPage "14740" @default.
- W2885483780 abstract "Analogous to the c-Myc (Myc)/Max family of bHLH-ZIP transcription factors, there exists a parallel regulatory network of structurally and functionally related proteins with Myc-like functions. Two related Myc-like paralogs, termed MondoA and MondoB/carbohydrate response element-binding protein (ChREBP), up-regulate gene expression in heterodimeric association with the bHLH-ZIP Max-like factor Mlx. Myc is necessary to support liver cancer growth, but not for normal hepatocyte proliferation. Here, we investigated ChREBP's role in these processes and its relationship to Myc. Unlike Myc loss, ChREBP loss conferred a proliferative disadvantage to normal murine hepatocytes, as did the combined loss of ChREBP and Myc. Moreover, hepatoblastomas (HBs) originating in myc-/-, chrebp-/-, or myc-/-/chrebp-/- backgrounds grew significantly more slowly. Metabolic studies on livers and HBs in all three genetic backgrounds revealed marked differences in oxidative phosphorylation, fatty acid β-oxidation (FAO), and pyruvate dehydrogenase activity. RNA-Seq of livers and HBs suggested seven distinct mechanisms of Myc-ChREBP target gene regulation. Gene ontology analysis indicated that many transcripts deregulated in the chrebp-/- background encode enzymes functioning in glycolysis, the TCA cycle, and β- and ω-FAO, whereas those dysregulated in the myc-/- background encode enzymes functioning in glycolysis, glutaminolysis, and sterol biosynthesis. In the myc-/-/chrebp-/- background, additional deregulated transcripts included those involved in peroxisomal β- and α-FAO. Finally, we observed that Myc and ChREBP cooperatively up-regulated virtually all ribosomal protein genes. Our findings define the individual and cooperative proliferative, metabolic, and transcriptional roles for the Extended Myc Network under both normal and neoplastic conditions." @default.
- W2885483780 created "2018-08-22" @default.
- W2885483780 creator A5019630947 @default.
- W2885483780 creator A5031584100 @default.
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- W2885483780 creator A5036171363 @default.
- W2885483780 creator A5048384848 @default.
- W2885483780 creator A5052519286 @default.
- W2885483780 creator A5077910504 @default.
- W2885483780 creator A5086726605 @default.
- W2885483780 creator A5087651973 @default.
- W2885483780 date "2018-09-01" @default.
- W2885483780 modified "2023-10-16" @default.
- W2885483780 title "Myc and ChREBP transcription factors cooperatively regulate normal and neoplastic hepatocyte proliferation in mice" @default.
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