Signal Transduction in the Liver: C/Ebpβ Modulates Cell Proliferation and Survival

Buck, Martina

doi:10.1053/jhep.2003.50155

Cited by 49 publications

(50 citation statements)

References 69 publications

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“…Furthermore, the latent immediate early transcription factors nuclear factor B (NFB), CCAAT/Enhancer Binding Protein ␤ (C/ EBP␤) proteins and signal transducers and activators of transcription 3 (Stat3) are activated through phosphorylation dependent signaling pathways. 2,[5][6][7] Several lines of evidence establish a critical role for TNF␣ and its rapidly activated downstream target, IL-6, in the transition of hepatocytes into the cell cycle following PHx. Activation of AP1 and NFB transcription factors, as well as DNA synthesis, can be inhibited by pretreatment of the mice with antibodies against TNF␣, 8 suggesting that this cytokine plays a central role in activating transcription factors required for initiation of liver regeneration.…”

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confidence: 99%

The CAR Nuclear Receptor and Hepatocyte Proliferation * #

et al. 2005

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confidence: 99%

The CAR Nuclear Receptor and Hepatocyte Proliferation * #

et al. 2005

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“…LAP* and LAP are two different forms of "liver activating protein," whereas LIP, "liver inhibitory protein," is a truncated isoform that serves as a naturally occurring dominant negative (24). The predicted molecular masses are 36, 33.5, and 16.5 kDa for the human proteins, respectively, although they are known to run anomalously on SDS-PAGE and are subject to post-translational modification (18,25). To provide a standard reference, a human cDNA beginning with the second methionine codon was expressed in HepG2 cells, and thus, should yield only the LAP and LIP isoforms.…”

Section: Atf3-fl Atf4 and C/ebp␤ Protein Content Responds To Aminomentioning

confidence: 99%

“…2D). The molecular basis for this heterogeneity remains to be established, but C/EBP␤ is known to be the target of post-translational modification (18,25).…”

Section: Atf3-fl Atf4 and C/ebp␤ Protein Content Responds To Aminomentioning

confidence: 99%

Amino Acid Deprivation Induces the Transcription Rate of the Human Asparagine Synthetase Gene through a Timed Program of Expression and Promoter Binding of Nutrient-responsive Basic Region/Leucine Zipper Transcription Factors as Well as Localized Histone Acetylation

Chen¹,

Pan²,

Dudenhausen

et al. 2004

Journal of Biological Chemistry

177

240

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Expression of human asparagine synthetase (ASNS), which catalyzes asparagine and glutamate biosynthesis, is transcriptionally induced following amino acid deprivation. Previous overexpression and electrophoresis mobility shift analysis showed the involvement of the transcription factors ATF4, C/EBP␤, and ATF3-FL through the nutrient-sensing response element-1 (NSRE-1) within the ASNS promoter. Amino acid deprivation caused an elevated mRNA level for ATF4, C/EBP␤, and ATF3-FL, and the present study established that the nuclear protein content for ATF4 and ATF3-FL were increased during amino acid limitation, whereas C/EBP␤-LIP declined slightly. The total amount of C/EBP␤-LAP protein was unchanged, but changes in the distribution among multiple C/EBP␤-LAP forms were observed. Overexpression studies established that ATF4, ATF3-FL, and C/EBP␤-LAP could coordinately modulate the transcription from the human ASNS promoter. Chromatin immunoprecipitation demonstrated that amino acid deprivation increased ATF3-FL, ATF4, and C/EBP␤ binding to the ASNS promoter and enhanced promoter association of RNA polymerase II, TATA-binding protein, and TFIIB of the general transcription machinery. A time course revealed a markedly different temporal order of interaction between these transcription factors and the ASNS promoter. During the initial 2 h, there was a 20-fold increase in ATF4 binding and a rapid increase in histone H3 and H4 acetylation, which closely paralleled the increased transcription rate of the ASNS gene, whereas the increase in ATF3-FL and C/EBP␤ binding was considerably slower and more closely correlated with the decline in transcription rate between 2 and 6 h. The data suggest that ATF3-FL and C/EBP␤ act as transcriptional suppressors for the ASNS gene to counterbalance the transcription rate activated by ATF4 following amino acid deprivation.

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“…C͞EBP␤ is an important effector of growth signals in experimental models of physiologic and neoplastic growth, the acutephase response, and metabolic homeostasis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Livers from C͞EBP␤ Ϫ/Ϫ mice exhibit a blunted regenerative response associated with prolonged hypoglycemia and altered expression of several cell-cycle-associated genes (10).…”

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Orthogonal analysis of C/EBPβ targets in vivo during liver proliferation

Friedman

Larris

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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CCAAT enhancer-binding protein ␤ (C͞EBP␤), a basic-leucine zipper transcription factor, is an important effector of signals in physiologic growth and cancer. The identification of direct C͞EBP␤ targets in vivo has been limited by functional compensation by other C͞EBP family proteins and the low stringency of the consensus sequence. Here we use the combined power of expression profiling and high-throughput chromatin immunoprecipitation to identify direct and biologically relevant targets of C͞EBP␤. We identified 25 potential C͞EBP␤ targets, of which 88% of those tested were confirmed as in vivo C͞EBP␤-binding sites. Six of these genes also displayed differential expression in C͞EBP␤ ؊/؊ livers. Computational analysis revealed that bona fide C͞EBP␤ target genes can be distinguished by the presence of binding motifs for specific additional transcription factors in the vicinity of the C͞EBP␤ site. This approach is generally applicable to the discovery of direct, biologically relevant targets of mammalian transcription factors.C CAAT enhancer-binding proteins (C͞EBPs) constitute a family of basic-leucine zipper (bZIP) transcription factors that are critical for the regulation of numerous biological processes, including differentiation, metabolic homeostasis, proliferation, tumorigenesis, inflammation, and apoptosis (1-9). C͞EBP proteins are regulated at multiple levels, including gene transcription, translation, and phosphorylation, in response to a variety of stimuli including hormonal, cytokine and growth factor-signaling pathways (1). C͞EBP proteins are able to form hetero-and homodimeric complexes with other C͞EBP family members, thereby creating additional diversity in target sequence recognition.C͞EBP␤ is an important effector of growth signals in experimental models of physiologic and neoplastic growth, the acutephase response, and metabolic homeostasis (1-11). Livers from C͞EBP␤ Ϫ/Ϫ mice exhibit a blunted regenerative response associated with prolonged hypoglycemia and altered expression of several cell-cycle-associated genes (10). In addition, a recent microarray analysis of human tumors has implicated C͞EBP␤ as a downstream mediator of cyclin D (12). Although these studies provide strong support for the role of C͞EBP␤ as a regulator of cell growth, at present, neither the mechanism by which C͞EBP␤ modulates the growth effects of cyclin D1 nor the targets of C͞EBP␤ in this pathway have been elucidated.A variety of approaches has been used to identify C͞EBP␤-binding sites, including cell culture systems, C͞EBP␤ Ϫ/Ϫ mice, and analyses of promoter sequences. However, several obstacles have limited the identification of direct C͞EBP␤-dependent transcriptional targets in vivo. All C͞EBP family members with the exception of C͞EBP possess identical in vitro DNA-binding affinity for C͞EBP consensus sequences, suggesting that other C͞EBP family members may be able to compensate for the loss of C͞EBP␤ (13). Second, the application of computational sequence analysis to identify C͞EBP promoter sequences has been impede...

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Signal Transduction in the Liver: C/Ebpβ Modulates Cell Proliferation and Survival

Cited by 49 publications

References 69 publications

The CAR Nuclear Receptor and Hepatocyte Proliferation * #

The CAR Nuclear Receptor and Hepatocyte Proliferation * #

Amino Acid Deprivation Induces the Transcription Rate of the Human Asparagine Synthetase Gene through a Timed Program of Expression and Promoter Binding of Nutrient-responsive Basic Region/Leucine Zipper Transcription Factors as Well as Localized Histone Acetylation

Orthogonal analysis of C/EBPβ targets in vivo during liver proliferation

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