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Organ Cross-Talk Regulates (Brain) Insulin Action
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
The seemingly paradoxical gene expression of Fgf21 caused by fasting (free fatty acids) and feeding signals (fructose, alcohol) suggests that FGF21 is elevated under a nutritional crisis, which includes energy restriction and overfeeding with liver-toxic fructose and alcohol. Since caloric restriction automatically entails a reduction of protein intake, which may be designated as a nutritional crisis as well, it was verified that circulating FGF21 concentrations are robustly induced by dietary protein restriction in rats, mice, and humans – without caloric restriction – which indicates FGF21 as an endocrine signal of dietary protein restriction (104). The general amino acid control pathway is induced by protein restriction and is required for activation of FGF21. The serine/threonine kinase general control nonderepressible 2 (GCN2) is a cellular kinase that phosphorylates the eukaryotic initiation factor 2 alpha (eIF2α) in response to depletion of cellular amino acids (105), with this mechanism coupling amino acid detection to metabolism (106–113). The phosphorylation of eIF2α results in the induction of the activating transcription factor 4 (ATF4), which binds to the FGF21 promoter that contains amino acid response elements (AARE) (114–117).
Proteasome and Protease Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
N. E. Franke, J. Vink, J. Cloos, Gertjan J. L. Kaspers
Mechanisms distinct of the proteasome itself have also been suggested to be involved in bortezomib sensitivity and resistance. A microarray study has shown that overexpression of activating transcription factor (ATF)3, ATF4, ATF5, c-Jun, JunD, and caspase-3 is correlated with bortezomib in B-cell lymphoma cells (89). Furthermore, overexpression of cyclin D1 might also increase bortezomib sensitivity in vitro and in vivo in a breast cancer model (90). In contrast overexpression of heat shock protein (HSP)27, HSP70, HSP90 and T-cell factor 4 is associated with bortezomib resistance in B-cell lymphoma cells (89). These data together suggest that although the proteasome conformation is very important in bortezomib sensitivity, other factors might also be involved in intrinsic and acquired bortezomib resistance.
Pathophysiology and Management of Shock
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
The third, PERK (PKR-like ER kinase), is a serine/threonine kinase that, like IRE1, oligomerizes on release of its BiP anchor and autoactivates by transphosphorylation. Its substrate is the eukaryotic translation initiation factor 2a (eIF2a), which in its naked form binds eIF2B to exchange GDP for GTP to become active. Activated eIF2a can then load tRNA-Met on to the 40S ribosome to initiate protein translation. Phosphorylation of eIF2a on serine 51 prevents it from interacting with eIF2B, thus shutting down general protein translation. However, protected translation from ATF4 (activating transcription factor 4) is enhanced following phosphorylation of eIF2a, because of the presence of an alternative open reading frame 5’ upstream in the ATF4 mRNA. As with both XBP-1 and ATF6, ATF4 increases the production of molecular chaperones and antioxidant systems, as well as being important in gluconeogenesis (47).
The PERK/ATF4/CHOP signaling branch of the unfolded protein response mediates cisplatin-induced ototoxicity in hair cells
Published in Drug and Chemical Toxicology, 2023
Yanji Qu, Shimin Zong, Zhe Wang, Peiyu Du, Yingying Wen, Hao Li, Nan Wu, Hongjun Xiao
To investigate the sequential expression changes of key UPR-related molecules, we performed RT-qPCR analysis and found that the mRNA expression levels of ATF4, CHOP and TXNIP were notably elevated in a time-dependent manner after cisplatin treatment, while those of ASK1 and ATF6 were not significantly altered (Figure 2(a)). Consistent with the mRNA results, western blot analysis further verified the time-dependent changes in the protein expression levels of ATF4 and CHOP after cisplatin treatment, while TXNIP, XBP1s and p-ASK1/ASK1 showed no significant change until the 48 h cisplatin treatment (Figure 2(b,c)). In addition, after treatment of OC-1 cells with cisplatin for 48 h, the expression levels of Bax and cleaved caspase-3, two key apoptosis-related proteins, were significantly increased in a time-dependent manner, while the expression levels of the anti-apoptotic protein Bcl-2 exhibited the opposite trend (Figure 2(d,e)). Together, the expression profile of ATF4 and CHOP was consistent with that observed for the apoptosis-related proteins.
Protective role of PERK-eIF2α-ATF4 pathway in chronic renal failure induced injury of rat hippocampal neurons
Published in International Journal of Neuroscience, 2023
Qi Chen, Jingjing Min, Ming Zhu, Zhanqin Shi, Pingping Chen, Lingyan Ren, Xiaoyi Wang
In this study, we established CRF rat model by adenine gavage. The findings demonstrated that the degree of neuronal damage was significantly increased in the CRF group, which was in accordance with the results of previous research.33,34 PERK is one of the major biochemical pathways in protein unfolding. PERK is activated through dimerization and phosphorylation, and activated PERK reduces translation by phosphorylating eIF2α, a factor that induces the translation of some special mRNAs including the activation transcription factor ATF4.35 The main function of ATF4 is to promote the gene expression of functional proteins,36 and then promote the activation of CHOP that mediates metabolism and apoptosis of cells.37,38 The results of Western blot in our study revealed that the expressions of p-PERK and p-eIF2α were significantly increased in the CRF group.
The role of autophagy in acute myeloid leukemia development
Published in Expert Review of Anticancer Therapy, 2023
Martyna Bednarczyk, Karolina Kociszewska, Olga Grosicka, Sebastian Grosicki
In about 20% of patients suffering from AML, mutated tyrosine kinase FLT3 (FMS-like tyrosine kinase 3) was observed, causing proliferation and survival of leukemic cells, which is associated with poor prognosis. Two FLT3-ITD (internal tandem duplication, ITD) or FLT3-TKD (tyrosine kinase domain-1, TKD1) mutations were detected. Mutated FLT3 kinase activity has been shown to increase basal levels of autophagy in AML cells, which is essential for the proliferation and survival of leukemic cells. Activating transcription factor 4 (ATF4) has been identified as an essential regulator of FLT3-ITD induced autophagy. Moreover, inhibition of autophagy or ATF4 inhibited the proliferation of AML cells and improved the viability of mice. Moreover, inhibition of autophagy in FLT3-TKD cells that are resistant to the FLT3 inhibitor (quizartinib) is also able to inhibit cell proliferation [56,59,60].