Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres

Tanaka, Takashi; Tsujimura, Tohru; Takeda, Kohsuke; Sugihara, Ayako; Maekawa, Akiko; Terada, Nobuyuki; Yoshida, Nobuaki; Akira, Shizuo

doi:10.1046/j.1365-2443.1998.00230.x

Cited by 161 publications

(137 citation statements)

References 36 publications

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“…This result is different from a previous Western blot study where CHOP protein induction during ER stress was completely abolished in their ATF4-null MEFs (32). The phenotypes of the two ATF4-null mice are very similar with both showing lens development defect and with the majority of homozygotes dying between E14.5 and birth (our ATF4 Ϫ/Ϫ mice birth rate: 6.5% versus Dr. J. M. Leiden, 7.5%) (23,33,34). Combined with the facts that in our ATF4 Ϫ/Ϫ MEFs, 58% of the coding region of ATF4 including the entire basic DNA binding domain and the leucine-zipper dimerization domain was substituted with a neomycin resistance gene, no ATF4 transcript was detected by Northern blotting (Fig.…”

Section: Atf4 Was Not Essential For Herp and Chop Induction During Ersupporting

confidence: 55%

Herp Is Dually Regulated by Both the Endoplasmic Reticulum Stress-specific Branch of the Unfolded Protein Response and a Branch That Is Shared with Other Cellular Stress Pathways

Hendershot

2004

Journal of Biological Chemistry

149

119

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The mammalian unfolded protein response (UPR) includes two major branches: one(s) specific to ER stress (Ire1/XBP-1 and ATF6-dependent), and one(s) shared by other cellular stresses (PERK/eIF-2␣ phosphorylationdependent). Here, we demonstrate that the ER-localized protein Herp represents a second target, in addition to CHOP, that is dually regulated by both the shared and the ER stress-specific branches during UPR activation. For the first time, we are able to assess the contribution of each branch of the UPR in the induction of these targets. We demonstrate that activation of the shared branch of the UPR alone was sufficient to induce Herp and CHOP. ATF4 was not required during ER stress when both branches were used but did contribute significantly to their induction. Conversely, stresses that activated only the shared branch of the UPR were completely dependent on ATF4 for CHOP and Herp induction. Thus, the shared and the ER stress-specific branches of the UPR diverge to regulate two groups of targets, one that is ATF6 and Ire1/XBP-1-dependent, which includes BiP and XBP-1, and another that is eIF-2␣ kinase-dependent, which includes ATF4 and GADD34. The two branches also converge to maximally up-regulate targets like Herp and CHOP. Finally, our studies reveal that a PERK-dependent target other than ATF4 is contributing to the cross-talk between the two branches of the UPR that has previously been demonstrated.

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Section: Atf4 Was Not Essential For Herp and Chop Induction During Ersupporting

confidence: 55%

Herp Is Dually Regulated by Both the Endoplasmic Reticulum Stress-specific Branch of the Unfolded Protein Response and a Branch That Is Shared with Other Cellular Stress Pathways

Hendershot

2004

Journal of Biological Chemistry

149

119

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“…Disrupted Rhythm in the Expression of Circadian Clock Genes in Atf4-null Cells-Mice lacking ATF4 have abnormal phenotypes such as microphthalmia, fetal anemia, and osteogenesis imperfects (11,(21)(22)(23). Furthermore, Atf4-null (Atf4 Ϫ/Ϫ ) mice died shortly after birth.…”

Section: Resultsmentioning

confidence: 99%

“…Mice lacking ATF4 display various abnormal phenotypes such as microphthalmia, fetal anemia, and osteogenesis imperfect (11,(21)(22)(23). However, Clock/Clock mice do not display such abnormal phenotypes despite low levels of ATF4.…”

Section: Discussionmentioning

confidence: 99%

cAMP-response Element (CRE)-mediated Transcription by Activating Transcription Factor-4 (ATF4) Is Essential for Circadian Expression of the Period2 Gene

Koyanagi

Hamdan

Horiguchi

et al. 2011

Journal of Biological Chemistry

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Activating transcription factor (ATF)/cAMP-response element (CRE)-binding (CREB) proteins induce the CRE-mediated gene transcription depending on the cAMP stimulation. cAMPdependent signaling oscillates in a circadian manner, which in turn also sustains core oscillation machinery of the circadian clock. Here, we show that among the ATF/CREB family proteins, ATF4 is essential for the circadian expression of the Period2 (Per2) gene, a key component of the circadian clock. Transcription of the Atf4 gene was regulated by core components of the circadian clock, and its expression exhibited circadian oscillation in mouse tissues as well as embryonic fibroblasts. ATF4 bound to the CRE of the Per2 promoter in a circadian time-dependent manner and periodically activated the transcription of the Per2 gene. Consequently, the oscillation of the Per2 expression was attenuated in embryonic cells prepared from Atf4-null mice. Furthermore, the loss of ATF4 also disrupted the rhythms in the expression of other clock genes. These results suggest that ATF4 is a component responsible for sustaining circadian oscillation of CRE-mediated gene expression and also constitute a molecular link connecting cAMP-dependent signaling to the circadian clock.Genetic and molecular approaches have identified a basic mechanism of the circadian oscillator that is governed by interconnected transcriptional and translational feedback loops (1, 2). Gene products of Clock and Bmal1 (also known as Arntl) form a heterodimer that activates the transcription of Period (Per) and Cryptochrome (Cry) genes. Once PER and CRY proteins have reached a critical concentration, they attenuate CLOCK/BMAL1-mediated transactivation, thus generating circadian oscillation in their own transcription. Rev-erb␣ (known as Nrd1d1) is also activated by CLOCK/BMAL1 and transrepressed by PER and CRY, resulting in circadian oscillation in the expression of Rev-erb␣. In turn, REV-ERB␣ periodically represses Bmal1 transcription, thereby interconnecting the positive and negative loops (3). Like the mechanism of Reverb␣ transcription, clock genes comprising the core oscillation loop transduce downstream events by regulating the expression of clock-controlled output genes (4). cAMP-dependent signaling is involved in the circadian output pathways, but the cAMP signaling subsequently sustains the core oscillation loops in the suprachiasmatic nucleus (SCN), 3 the center of the mammalian circadian clock (5, 6). However, the regulation mechanism of cAMP to sustain the circadian oscillator remains to be elucidated.The intracellular accumulation of cAMP induces CRE-mediated gene expression via ATF/CREB protein activation (7). ATF/CREB proteins belong to the bZIP transcription factor superfamily, and they are characterized by a conserved domain including highly charged basic amino acids that are required for DNA recognition at the TGACGT(C/A)(G/A) sequence (8). Although the phosphorylated states of CREB in the SCN vary in a circadian manner (5), the functional importance of the transcriptional...

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“…Indeed, overexpression of ATF4 is insufficient to activate the full complement of ESR genes 93 and the gross phenotype of ATF4 À/À mice 106 is different from that of PERK À/À mice 99 and eIF2a A/A knockin mice, which harbor a homozygous Ser 51 -Ala 51 mutation at the critical phosphorylation site in the endogenous eIF2a locus. 107 EIF2a A/A cells fail to upregulate about one-third of the genes normally induced by ER stress and are hypersensitive to ER stress-induced apoptosis, 107 indicating that translational control impacts on a wide range of ER stressresponsive genes.…”

Section: Esr In Mammalsmentioning

confidence: 99%

Cellular response to endoplasmic reticulum stress: a matter of life or death

2006

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The proper functioning of the endoplasmic reticulum (ER) is critical for numerous aspects of cell physiology. Accordingly, all eukaryotes react rapidly to ER dysfunction through a set of adaptive pathways known collectively as the ER stress response (ESR). Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger programmed cell death, or apoptosis. ER stress and the apoptotic program coupled to it have been implicated in many important pathologies but the regulation and execution of ER stressinduced apoptosis in mammals remain incompletely understood. Here, we review what is known about the ESR in both yeast and mammals, and highlight recent findings on the mechanism and pathophysiological importance of ER stressinduced apoptosis.

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Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres

Cited by 161 publications

References 36 publications

Herp Is Dually Regulated by Both the Endoplasmic Reticulum Stress-specific Branch of the Unfolded Protein Response and a Branch That Is Shared with Other Cellular Stress Pathways

Herp Is Dually Regulated by Both the Endoplasmic Reticulum Stress-specific Branch of the Unfolded Protein Response and a Branch That Is Shared with Other Cellular Stress Pathways

cAMP-response Element (CRE)-mediated Transcription by Activating Transcription Factor-4 (ATF4) Is Essential for Circadian Expression of the Period2 Gene

Cellular response to endoplasmic reticulum stress: a matter of life or death

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