Reciprocal Regulation of Adipogenesis by Myc and C/EBPα

Freytag, Svend O.; Geddes, Tim J.

doi:10.1126/science.256.5055.379

Cited by 283 publications

(194 citation statements)

References 30 publications

(8 reference statements)

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“…Besides cyclin D1 (Philipp et al, 1994), other genes repressed in c-Myc-transformed cells included those that encode cell adhesion proteins, such as the ␤1 integrin subunit (Judware and Culp, 1995); molecules of the immune system, such as major histocompatibility complex class I and lymphocyte function-associated antigen-1 (Bernards et al, 1986;Versteeg et al, 1988;Inghirami et al, 1990); and cell cycle regulators, such as C/EBP␣ (Freytag and Geddes, 1992) and c-Myc itself (Penn et al, 1990). These findings suggested that gene repression contributes significantly to the phenotype of c-Myc transformed cells.…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

Huerta¹,

Muñoz²,

Tapia

et al. 2007

MBoC

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Recent reports have indicated the participation of tight junction (TJ) proteins in the regulation of gene expression and cell proliferation. Here, we have studied the role of zona occludens (ZO)-2, a TJ peripheral protein, in the regulation of cyclin D1 transcription. We found that ZO-2 down-regulates cyclin D1 transcription in a dose-dependent manner. To understand how ZO-2 represses cyclin D1 promoter activity, we used deletion analyses and found that ZO-2 negatively regulates cyclin D1 transcription via an E box and that it diminishes cell proliferation. Because ZO-2 does not associate directly with DNA, electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) assay were used to identify the transcription factors mediating the ZO-2-repressive effect. c-Myc was found to bind the E box present in the cyclin D1 promoter, and the overexpression of c-Myc augmented the inhibition generated by ZO-2 transfection. The presence of ZO-2 and c-Myc in the same complex was further demonstrated by immunoprecipitation. ChIP and reporter gene assays using histone deacetylases (HDACs) inhibitors demonstrated that HDACs are necessary for ZO-2 repression and that HDAC1 is recruited to the E box. We conclude that ZO-2 down-regulates cyclin D1 transcription by interacting with the c-Myc/E box element and by recruiting HDAC1.

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Section: Discussionmentioning

confidence: 99%

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

Huerta¹,

Muñoz²,

Tapia

et al. 2007

MBoC

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“…It is likely that C/EBPa plays an important role in the development and function of fat and liver tissue. Two previous studies that examined whether ectopic expression of C/EBPc~ could promote the adipogenic program in 3T3-L 1 adipoblasts gave disparate results Freytag and Geddes 1992}. One study showed that conditional activation of a C/EBP~t--estrogen receptor fusion protein suppressed 3T3-L1 adipoblast growth~ however, it was not sufficient for overt differentiation (Umek et al 19911.…”

Section: ;mentioning

confidence: 99%

“…Others have encountered this problem (Weintraub et al 1989). Therefore, isolated colonies were examined for expression of the proviral WZLneo-C/EBPa RNA using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis as described previously (Freytag and Geddes 1992). Although the primers used in these analyses hybridize to the neomycin gene, they detect the same RNA transcript that generates C/EBPa (because of the dicistronic nature of proviral RNA transcript).…”

Section: Development Of the Adipocyte Morphology Requires Expression mentioning

confidence: 99%

Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells.

Freytag

Paielli²,

Gilbert³

1994

Genes Dev.

414

294

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The CCAAT/enhancer-binding protein ot (C/EBPa) has been implicated in the regulation of adipoblast differentiation. In this study we investigate the potential of C/EBPot to promote the adipogenic program in a variety of fibroblastic cells. Transduction of the C/EBPc~ gene into eight mouse fibroblastic cell lines by retroviruses and DNA transfection generates adipocyte colonies at variable frequencies. The most dramatic results are obtained with NIH-3T3 cells, in which the percentage of G418-resistant colonies that exhibit the adipocyte morphology is reproducibly >50% when the C/EBPc~ gene is transduced by retroviruses. The ability to promote the adipogenic program requires the potent transcriptional activation domain of C/EBPa and is not observed with C/EBPI3. Paradoxically, in spite of its antimitogenic effects, clonal cell lines that stably express high amounts of C/EBPa can readily be generated. Stable expression of C/EBPot in BALB/c-3T3 cells dramatically enhances their ability to terminally differentiate into adipocytes. The results demonstrate that C/EBPa can efficiently promote the adipogenic program in a variety of mouse fibroblastic cells, including those that have little or no spontaneous capacity to undergo adipogenesis.

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“…C/EBPα is a strong inhibitor of cell proliferation [4][5][6]. It initiates growth arrest by stabilizing p21, and by disrupting E2F transcriptional complexes during the G1 phase of the cell cycle [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Expression of antisense C/EBPα RNA prevents both growth arrest and terminal differentiation of 3T3-L1 adipocytes [18]. In addition, C/EBPα is critical in regulating the differentiation of preadipocytes, myeloid cells, hepatocytes and pneumocytes [3,5,[19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

C/EBPαp30 plays transcriptional regulatory roles distinct from C/EBPαp42

et al. 2007

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CCAAT/enhancer binding protein α (C/EBPα) is a transcriptional regulatory factor that inhibits cell proliferation, and alternative translational initiation produces two polypeptides, C/EBPαp30 and C/EBPαp42. By expression profiling, it was revealed that C/EBPαp30 specifically inhibited a unique set of genes, including MPP11, p84N5 and SMYD2, which were not affected by C/EBPαp42 in both QSG-7701 hepatocyte cell line and QGY-7703 hepatoma cells. Semiquantitative RT-PCR analysis independently confirmed these results. Chromatin immunoprecipitation assay showed that C/EBPαp30 bound to the promoters of these genes more strongly than C/EBPαp42. In clinical hepatoma samples in which C/EBPα was downregulated, all three genes specifically inhibited by C/EBPαp30 were upregulated. However, repression of MPP11, p84N5 and SMYD2 genes might not be directly involved in C/EBPαp30-mediated growth inhibition. Our data suggest that C/EBPαp30 regulates a unique set of target genes and is more than a dominant-negative regulator of C/EBPαp42.

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Reciprocal Regulation of Adipogenesis by Myc and C/EBPα

Cited by 283 publications

References 30 publications

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

Cyclin D1 Is Transcriptionally Down-Regulated by ZO-2 via an E Box and the Transcription Factor c-Myc

Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells.

C/EBPαp30 plays transcriptional regulatory roles distinct from C/EBPαp42

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