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

Chun-xi, Wang; Chen, Xiaotao; Wang, Yanping; Ju, Gong; Hu, Gengxi

doi:10.1038/sj.cr.7310121

Cited by 18 publications

(16 citation statements)

References 37 publications

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“…LIP expression is also elevated after UV irradiation, suggesting that decreased eIF2 ternary complex levels during cellular stress exacerbate this phenomenon (54). The related gene C/EBP␣ and its encoded protein isoforms are also translationally regulated by a 5Ј-proximal uORF (28,37,55).…”

Section: Translation Reinitiation and Differential Cds Translationmentioning

confidence: 99%

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

Young

Wek

2016

Journal of Biological Chemistry

331

313

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Translation regulation largely occurs during initiation, which features ribosome assembly onto mRNAs and selection of the translation start site. Short, upstream ORFs (uORFs) located in the 5-leader of the mRNA can be selected for translation. Multiple transcripts associated with stress amelioration are preferentially translated through uORF-mediated mechanisms during activation of the integrated stress response (ISR) in which phosphorylation of the ␣ subunit of eIF2 results in a coincident global reduction in translation initiation. This review presents key features of uORFs that serve to optimize translational control that is essential for regulation of cell fate in response to environmental stresses.Multiple genome-wide analyses, including those utilizing ribosome and polysome profiling and mass spectrometry approaches, have provided evidence demonstrating that translation is a major regulator of gene expression (1-5). In addition to protein coding sequences (CDSs), 2 another class of ORFs suggested to be translated at high frequency consists of short, upstream ORFs (uORFs) that are located within the 5Ј-leader of mRNAs (3-6). Over 40% of mammalian mRNAs contain uORFs, illustrating that uORFs are prevalent genome-wide and can serve as major regulators of translation (5,7,8). Approximation of uORF prevalence has relied upon the use of an AUG to denote the uORF start codon; however, recent ribosome profiling studies indicate that non-canonical initiation codons (e.g. CUG, UUG, and GUG) can also serve as competent sites of translation initiation (3, 4, 6). These findings suggest that the magnitude of uORF prevalence and the contribution of uORF translation in the regulation of gene expression have likely been underestimated.Typically, uORFs are considered to be inhibitors of downstream translation initiation at CDSs. The inhibitory effect of uORFs is attributed to the fact that in eukaryotes the 43S preinitiation complex binds to the 5Ј-cap structure of the mRNA, then scans processively 5Ј to 3Ј and initiates translation at the first encountered initiation codon that is in an optimal context (9). The 43S preinitiation complex is composed of multiple factors including eIF3, eIF1, eIF1A, the eIF2⅐GTP⅐Met-tRNA i Met ternary complex, and the small 40S ribosomal subunit (10). Disassociation of the eIF2 ternary complex and other critical initiation factors during translation of constitutively repressing uORFs is suggested to be the cause of the low levels of subsequent translation reinitiation at downstream coding sequences.Although uORFs can serve as repressors of CDS translation in a constitutive manner, there are also examples of uORFs that serve as dampeners in a controlled fashion or even promote translation initiation at the CDS in response to environmental stresses (4, 5, 11). Based on these studies, uORFs can have the following core properties that are critical for translational control (Fig. 1). 1) They enhance reinitiation after uORF translation, allowing for degrees of translation initiation at the downstre...

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Section: Translation Reinitiation and Differential Cds Translationmentioning

confidence: 99%

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

Young

Wek

2016

Journal of Biological Chemistry

331

313

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“…Plasmids pcDNA-C/EBPα and pcDNA-C/EBPαp30 expressing two isoforms of C/EBPα, C/EBPα and C/EBPαp30, respectively; and pcDNA-C/EBPβ expressing C/EBPβ were all kindly provided by G Hu [31]. pCS2+-SIRT1 expressing SIRT1 was constructed by insertion of SIRT1 cDNA fragment cut from pBabepuro-SIRT1 [4] into pCS2+ at the BamHI site.…”

Section: Methodsmentioning

confidence: 99%

C/EBPα regulates SIRT1 expression during adipogenesis

et al. 2010

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SIRT1 plays an important role in adipogenesis, but how SIRT1 is regulated in adipogenesis is largely unknown. In this study, we show that both SIRT1 protein and mRNA levels were increased along with CCAAT/enhancer-binding protein α (C/EBPα) during adipocyte differentiation. C/EBPα, but not C/EBPαp30, activated SIRT1 promoter in both HeLa cells and 3T3-L1 preadipocytes. Furthermore, C/EBPα upregulated SIRT1 mRNA and protein levels in HeLa cells and increased SIRT1 expression in a p53-independent manner in Soas2 cells. In preadipocytes, ectopic expression of C/EBPα upregulated SIRT1 protein level and knockdown of C/EBPα led to the decrease of SIRT1 protein level. Moreover, by promoter deletion analysis, gel shift assay and chromatin immunoprecipitation, we found that C/EBPα bound to the SIRT1 promoter at a consensus C/EBPα binding site. These data demonstrate that C/ EBPα regulates SIRT1 expression during adipogenesis by directly binding to the SIRT1 promoter.

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“…C/EBP␣ transcription factor functions are associated with the regulation of energy metabolism by positively regulating genes linked to metabolic functions such as phosphoenolpyruvate carboxykinase and tyrosine aminotransferase (Darlington et al 1995;Wang et al 1995Wang et al , 2007. On the other hand, C/EBP␣ was reported to be a major dominant repressor of the liver fatty acid binding protein in HepG2 cells (Guzman et al 2013).…”

Section: C/ebp␣ and Lip Block C/ebp␤ Transcriptional Regulation Of P2mentioning

confidence: 98%

C/EBPβ regulates P2X7 receptor expression in response to glucose challenge in intestinal epithelial cells

BilodeauMaude

ArguinGuillaume

GendronFernand-Pierre

2015

Biochem. Cell Biol.

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Activation of the ATP-dependent P2X7 receptor modulates glucose transport in intestinal epithelial cells through the downregulation of glucose transporter GLUT2. In the present study, we show that an increase in glucose concentration stimulates P2X7 receptor transcription via modulation of CCAAT/enhancer binding proteins (C/EBPs) α and β expression. The described human P2X7 receptor promoter region (GenBank Y12851) was cloned upstream of a luciferase reporter gene in pGL4.10 plasmid and used to determine whether C/EBPs, namely C/EBPα and C/EBPβ, are able to stimulate the transcription of P2X7 receptor. Results show that C/EBPβ was the main regulator of P2X7 receptor expression in response to a glucose challenge. Chromatin immunoprecipitation (ChIP) assays further revealed that C/EBPβ occupied the -213 to +6 nt P2X7 promoter region. Surprisingly, C/EBPα was also able to bind this region as revealed by ChIP assays, but without inducing receptor transcription. In fact, C/EBPα and the C/EBPβ-LIP isoform blocked the C/EBPβ-dependent regulation of P2X7 receptor transcription. These findings suggest that glucose is not only the major source of energy for cell function but may also act as a signaling molecule to stimulate the expression of regulatory proteins.

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

Cited by 18 publications

References 37 publications

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

C/EBPα regulates SIRT1 expression during adipogenesis

C/EBPβ regulates P2X7 receptor expression in response to glucose challenge in intestinal epithelial cells

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