scholarly journals Activating transcription factor 4 increases chemotherapeutics resistance of human hepatocellular carcinoma

2012 ◽  
Vol 13 (6) ◽  
pp. 435-442 ◽  
Author(s):  
Zhuhong Zhang ◽  
Jing Yin ◽  
Chunyan Zhang ◽  
Ning Liang ◽  
Nan Bai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Human Hepatocellular Carcinoma ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

scholarly journals Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress

2004 ◽  
Vol 24 (17) ◽  
pp. 7469-7482 ◽  
Author(s):  
Jaime D. Blais ◽  
Vasilisa Filipenko ◽  
Meixia Bi ◽  
Heather P. Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Microarray Analysis ◽  
Initiation Factor ◽  
Hypoxic Stress ◽  
Unfolded Protein ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Transcription Factor 4

ABSTRACT Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2α (eIF2α) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2α at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2α was able to attenuate the phosphorylation of eIF2α and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2α-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.

scholarly journals Role of Activating Transcription Factor 4 in Murine Choroidal Neovascularization Model

2021 ◽  
Vol 22 (16) ◽  
pp. 8890
Author(s):  
Hiroto Yasuda ◽  
Miruto Tanaka ◽  
Anri Nishinaka ◽  
Shinsuke Nakamura ◽  
Masamitsu Shimazawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Er Stress ◽  
Choroidal Neovascularization ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Activating Transcription Factor 4 ◽  
Age Related ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

Neovascular age-related macular degeneration (nAMD) featuring choroidal neovascularization (CNV) is the principal cause of irreversible blindness in elderly people in the world. Integrated stress response (ISR) is one of the intracellular signals to be adapted to various stress conditions including endoplasmic reticulum (ER) stress. ISR signaling results in the upregulation of activating transcription factor 4 (ATF4), which is a mediator of ISR. Although recent studies have suggested ISR contributes to the progression of some age-related disorders, the effects of ATF4 on the development of CNV remain unclear. Here, we performed a murine model of laser-induced CNV and found that ATF4 was highly expressed in endothelial cells of the blood vessels of the CNV lesion site. Exposure to integrated stress inhibitor (ISRIB) reduced CNV formation, vascular leakage, and the upregulation of vascular endothelial growth factor (VEGF) in retinal pigment epithelium (RPE)-choroid-sclera complex. In human retinal microvascular endothelial cells (HRMECs), ISRIB reduced the level of ATF4 and VEGF induced by an ER stress inducer, thapsigargin, and recombinant human VEGF. Moreover, ISRIB decreased the VEGF-induced cell proliferation and migration of HRMECs. Collectively, our findings showed that pro-angiogenic effects of ATF4 in endothelial cells may be a potentially therapeutic target for patients with nAMD.

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