Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

Dey, Souvik; Savant, Sudha S.; Teske, Brian F.; Hatzoglou, Maria; Calkhoven, Cornelis F.; Wek, Ronald C.

doi:10.1074/jbc.m112.351783

Cited by 40 publications

(38 citation statements)

References 65 publications

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“…After translation of the uORF, a number of 40S ribosomes are suggested to scan past the initiation codon of the LAP isoform before reacquiring a new eIF2⅐GTP⅐Met-tRNA i Met complex and begin translation at the initiation codon of LIP. 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%

“…For example, ATF4 expression is potently induced during endoplasmic reticulum stress, but there are only low levels of ATF4 expression during UV irradiation (54,81). Both conditions induce robust eIF2␣-P, and preferential translation of ATF4 mRNA occurs with either stress (81).…”

Section: Other Complexities Of Gene Expression Regulated By Uorfsmentioning

confidence: 99%

“…Both conditions induce robust eIF2␣-P, and preferential translation of ATF4 mRNA occurs with either stress (81). However, increased LIP expression and binding to the ATF4 promoter during UV irradiation repress ATF4 transcription (54). Lowered levels of ATF4 mRNA available for translation during UV stress thus result in negligible ATF4 protein and transcriptional activity.…”

Section: Other Complexities Of Gene Expression Regulated By Uorfsmentioning

confidence: 99%

See 2 more Smart Citations

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

Young

Wek

2016

Journal of Biological Chemistry

Self Cite

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%

Section: Other Complexities Of Gene Expression Regulated By Uorfsmentioning

confidence: 99%

Section: Other Complexities Of Gene Expression Regulated By Uorfsmentioning

confidence: 99%

See 1 more Smart Citation

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

Young

Wek

2016

Journal of Biological Chemistry

Self Cite

331

313

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“…In light of this mechanism, we sought to determine whether TGR5-dependent activation of the mTOR pathway could be responsible for the increase in LIP in our model. Stimufactors (52)(53)(54)(55). We first investigated whether TGR5 could regulate C/EBPβ expression.…”

Section: Tgr5mentioning

confidence: 99%

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

Perino¹,

Pols²,

Nomura³

et al. 2014

J. Clin. Invest.

183

128

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“…We therefore concluded that the 33 kDa band represented LAP and the 37 kDa band LAP*, as previous studies indicated that p33 is mainly translated in mouse embryonic fibroblasts (MEF), NIH3T3, and 3T3-L1 cells. (30)(31)(32)(33) No band corresponding to LIP was detected (data not shown). Mouse C/EBPb is known to be localized in the nucleus, which was confirmed by immunostaining using 7H5 and 7D2 monoclonal antibody clones (Fig.…”

Section: Resultsmentioning

confidence: 89%

Production of a Monoclonal Antibody for C/EBPβ: The Subnuclear Localization of C/EBPβ in Mouse L929 Cells

Harada

Okazaki

Okada

et al. 2014

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

Cited by 40 publications

References 65 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

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

Production of a Monoclonal Antibody for C/EBPβ: The Subnuclear Localization of C/EBPβ in Mouse L929 Cells

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