Impaired Energy Homeostasis in C/EBPα Knockout Mice

Wang, Nai-dy; Finegold, Milton J.; Bradley, Allan; Ou, Ching Nan; Abdelsayed, S; Wilde, Margaret; Taylor, Lorna; Wilson, Debra Rose; Darlington, Gretchen J.

doi:10.1126/science.7652557

Cited by 883 publications

(696 citation statements)

References 25 publications

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“…As FMIP influences myeloid differentiation as well, we examined the common key factors in both differentiation systems. One candidate is a protein belonging to the C/EBP family (Cao et al, 1991;Wang et al, 1995;Tenen et al, 1997;Lane et al, 1999), as it has been demonstrated that timely expression of C/ EBPalpha and C/EBPbeta is essential for adipocyte differentiation (Fux et al, 2004;Mori et al, 2005). Therefore, we examined the expression of C/EBPalpha and C/EBPbeta during differentiation in FMIP-overexpressing and knockdown cells.…”

Section: Fmip Influences the Expression Of C/ebpalpha Gene During Adimentioning

confidence: 99%

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

et al. 2006

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Fms interacting protein (FMIP) is a substrate for Fms tyrosine kinase, and a nuclear/cytoplasm shuttling protein with a leucine zipper. As the phosphorylation of FMIP is observed in insulin-stimulated preadipocytes, we examined the role of FMIP in adipocyte differentiation, using the mesenchymal multipotent stem cells, C2C12 cells, that can differentiate into adipocytes, muscle cells and osteoblasts. Ectopic expression of FMIP in C2C12 impairs the adipocyte differentiation induced by treatment with insulin, dexamethasone and 3-isobutyl-1-methylxanthine. These cells exhibit muscle phenotype with multinuclear morphology. Furthermore, knockdown of endogenous FMIP expression by small interfering RNA improves adipocytic lineage commitment of C2C12 cells, while impairing muscle differentiation. Upon stimulation with insulin, CCAAT/enhancer binding protein (C/EBP)-beta, but not C/EBPalpha, is upregulated in cells expressing ectopic FMIP, whereas in FMIP knockdown cells, C/EBPalpha is constitutively expressed. Ectopic expression of C/EBPalpha counteracts the effects of FMIP, whereas C/EBPalpha knockdown partially mimics the effects of FMIP in this system. Northern blot analysis and reverse transcriptase-polymerase chain reaction study reveal that ectopic FMIP-expressing cells do not contain the polyadenylated C/EBPalpha mRNA, but contain the C/EBPalpha pre-mRNA, suggesting that FMIP plays a role in RNA processing and/or export. Indeed, a member of the THO complex that plays a role in mRNA export, THOC1, is co-precipitated with FMIP. The data we have acquired on FMIP suggest that it is a target for tyrosine kinase receptors that potentiate mRNA export.

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Section: Fmip Influences the Expression Of C/ebpalpha Gene During Adimentioning

confidence: 99%

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

et al. 2006

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“…Members of the C/EBP family are known to have an essential role in adipose tissue development (Cao et al, 1991;Samuelsson et al, 1991;Umek et al, 1991;Freytag and Geddes, 1992;Wang et al, 1995;Yeh et al, 1995) and FUS-CHOP blocks di erentiation of adipogenic precursors in tissue culture (Kuroda et al, 1997;Adelmant et al, 1998). Whereas interference with the normal process of di erentiation may contribute to the oncogenic potential of FUS-CHOP fusion protein, it is a property that they share with the nontransforming germline CHOP gene product (Zinszner et al, 1994;Batchvarova et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice

et al. 2000

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The characteristic t(12;16)(q13;p11) chromosomal translocation, which leads to gene fusion that encodes the FUS-CHOP chimeric protein, is associated with human liposarcomas. The altered expression of FUS-CHOP has been implicated in a characteristic subgroup of human liposarcomas. We have introduced the FUS-CHOP transgene into the mouse genome in which the expression of the transgene is successfully driven by the elongation factor 1a (EF1a) promoter to all tissues. The consequent overexpression of FUS-CHOP results in most of the symptoms of human liposarcomas, including the presence of lipoblasts with round nuclei, accumulation of intracellular lipid, induction of adipocyte-speci®c genes and a concordant block in the di erentiation program. We have demonstrated that liposarcomas in the FUS-CHOP transgenic mice express high levels of the adipocyte regulatory protein PPARg, whereas it is not expressed in embryonic ®broblasts from these animals following induction to di erentiation toward the adipocyte lineage, indicating that the in vitro system does not really re¯ect the in vivo situation and the developmental defect is downstream of PPARg expression. No tumors of other tissues were found in these transgenic mice despite widespread activity of the EF1a promoter. This establishes FUS-CHOP overexpression as a key determinant of human liposarcomas and provide the ®rst in vivo evidence for a link between a fusion gene created by a chromosomal translocation and a solid tumor.

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“…Although tissue expression patterns of these members often overlap, recent studies using gene knockout analysis of C/EBPs in mice revealed that C/EBPs differ significantly in their physiological functions and in their downstream target genes. For example, mice lacking C/EBP␣ die shortly after birth due to severe hypoglycemia and the absence of glycogen storage in liver (23), whereas knockout of C/EBP␤ causes defects in female reproduction (18).…”

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confidence: 99%

C/EBPβ, When Expressed from the C/ebpα Gene Locus, Can Functionally Replace C/EBPα in Liver but Not in Adipose Tissue

Chen

Johnson

et al. 2000

Molecular and Cellular Biology

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Knockout of C/EBP␣ causes a severe loss of liver function and, subsequently, neonatal lethality in mice. By using a gene replacement approach, we generated a new C/EBP␣-null mouse strain in which C/EBP␤, in addition to its own expression, substituted for C/EBP␣ expression in tissues. The homozygous mutant mice C/ebp␣ ␤/␤ are viable and fertile and show none of the overt liver abnormalities found in the previous C/EBP␣-null mouse line. Levels of hepatic PEPCK mRNA are not different between C/ebp␣ ␤/␤ and wild-type mice. However, despite their normal growth rate, C/ebp␣ ␤/␤ mice have markedly reduced fat storage in their white adipose tissue (WAT). Expression of two adipocyte-specific factors, adipsin and leptin, is significantly reduced in the WAT of C/ebp␣ ␤/␤ mice. In addition, expression of the non-adipocyte-specific genes for transferrin and cysteine dioxygenase is reduced in WAT but not in liver. Our study demonstrates that when expressed from the C/ebp␣ gene locus, C/EBP␤ can act for C/EBP␣ to maintain liver functions during development. Moreover, our studies with the C/ebp␣ ␤/␤ mice provide new insights into the nonredundant functions of C/EBP␣ and C/EBP␤ on gene regulation in WAT.

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Impaired Energy Homeostasis in C/EBPα Knockout Mice

Cited by 883 publications

References 25 publications

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

FMIP controls the adipocyte lineage commitment of C2C12 cells by downmodulation of C/EBPalpha

The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice

C/EBPβ, When Expressed from the C/ebpα Gene Locus, Can Functionally Replace C/EBPα in Liver but Not in Adipose Tissue

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