scholarly journals Effect of Orexin-A on Cortisol Secretion in H295R Cells via p70S6K/4EBP1 Signaling Pathway

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Xiaocen Chang ◽  
Yuyan Zhao ◽  
Lei Guo
Keyword(s):  
Signaling Pathway ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Cortisol Secretion ◽  
Adrenocortical Cells ◽  
Orexin A ◽  
Eukaryotic Translation ◽  
Mitogen Activated Protein ◽  
H295r Cells

Orexin-A is a neuropeptide that orchestrates diverse central and peripheral processes. It is now clear that orexin system plays a central role in the regulation of endocrine, paracrine, and neurocrine. It is involved in the regulation of growth hormone, adrenocorticotropic hormone, thyroid, mineralocorticoid, and cortisol secretion. These hormones may also serve as a kind of signal linking energy balance regulation, reproduction, stress response, and cardiovascular regulation. Many studies have demonstrated the ability of orexin-A to regulate adrenocortical cells through the MAPK (mitogen-activated protein kinases) pathway. The aim of our study is to investigate the effect of orexin-A on cortisol secretion via the protein 70 ribosomal protein S6 kinase-1 (p70S6K) and eukaryotic translation initiation factor 4E binding proteins (4EBP1) signaling pathway in adrenocortical cells. We reported the first evidence that orexin-A stimulated p70S6K and 4EBP1 in human H295R adrenocortical cells in a concentration and time-dependent manner. 10−6 M orexin-A treatment for 1 hour was the most potent. Our results also indicated that p70S6K and 4EBP1 kinases participated in controlling cortisol secretion via OX1receptor in H295R cells, which implied important role of p70S6K and 4EBP1 kinases in regulating adrenal function induced by orexin-A.

scholarly journals Regulation of eIF2α Phosphorylation by MAPKs Influences Polysome Stability and Protein Translation

2021 ◽  
Author(s):  
Sana Parveen ◽  
Haripriya Parthasarathy ◽  
Dhiviya Vedagiri ◽  
Divya Gupta ◽  
Hitha Gopalan Nair ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Translation Regulation ◽  
Eukaryotic Translation ◽  
Eif2α Phosphorylation ◽  
Mitogen Activated Protein ◽  
Eukaryotic Translation Initiation ◽  
Polysome Stability

Regulation of protein translation occurs primarily at the level of initiation and is mediated by multiple signaling pathways, majorly mechanistic target of rapamycin complex 1 (mTORC1), mitogen-activated protein kinases (MAPKs), and the eukaryotic translation initiation factor eIF2. While mTORC1 and eIF2α influence the polysome stability, MAPKs influence the phosphorylation of the cap-binding protein eIF4E and are known to influence translation of only a small set of mRNAs. Here, we demonstrate that p38 MAPK and ERK1/2 regulate translation through integrated stress response (ISR) pathways. Dual inhibition (dual-Mi) of p38 MAPK and ERK1/2 caused substantial phosphorylation of eIF2α in a synergistic manner, resulting in near-absolute collapse of polysomes. This regulation was independent of Mnk1/2, a well-studied mediator of translation regulation by the MAPKs. Dual-Mi-induced polysome dissociation was far more striking than that caused by sodium arsenite, a strong inducer of ISR. Interestingly, induction of ISR caused increased p38 phosphorylation, and its inhibition resulted in stronger polysome dissociation, indicating the importance of p38 in the translation activities. Thus, our studies demonstrate a major, unidentified role for ERK1/2 and more particularly p38 MAPK in the maintenance of homeostasis of polysome association and translation activities.

scholarly journals IRE1α-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2α Phosphorylation and Suppresses Protein Synthesis

2015 ◽  
Vol 35 (16) ◽  
pp. 2761-2770 ◽  
Author(s):  
Jae-Seon So ◽  
Sungyun Cho ◽  
Sang-Hyun Min ◽  
Scot R. Kimball ◽  
Ann-Hwee Lee
Keyword(s):  
Protein Synthesis ◽  
Er Stress ◽  
Translational Control ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Regulatory Subunit ◽  
Dependent Manner ◽  
Eukaryotic Translation ◽  
Eif2α Phosphorylation ◽  
The Unfolded Protein Response

The unfolded protein response (UPR) regulates endoplasmic reticulum (ER) homeostasis and protects cells from ER stress. IRE1α is a central regulator of the UPR that activates the transcription factor XBP1s through an unconventional splicing mechanism using its endoribonuclease activity. IRE1α also cleaves certain mRNAs containing XBP1-like secondary structures to promote the degradation of these mRNAs, a process known as regulated IRE1α-dependent decay (RIDD). We show here that the mRNA of CReP/Ppp1r15b, a regulatory subunit of eukaryotic translation initiation factor 2α (eIF2α) phosphatase, is a RIDD substrate. eIF2α plays a central role in the integrated stress response by mediating the translational attenuation to decrease the stress level in the cell. CReP expression was markedly suppressed in XBP1-deficient mice livers due to hyperactivated IRE1α. Decreased CReP expression caused the induction of eIF2α phosphorylation and the attenuation of protein synthesis in XBP1-deficient livers. ER stress also suppressed CReP expression in an IRE1α-dependent manner, which increased eIF2α phosphorylation and consequently attenuated protein synthesis. Taken together, the results of our study reveal a novel function of IRE1α in the regulation of eIF2α phosphorylation and the translational control.

scholarly journals Mnk2 and Mnk1 Are Essential for Constitutive and Inducible Phosphorylation of Eukaryotic Initiation Factor 4E but Not for Cell Growth or Development

2004 ◽  
Vol 24 (15) ◽  
pp. 6539-6549 ◽  
Author(s):  
Takeshi Ueda ◽  
Rie Watanabe-Fukunaga ◽  
Hidehiro Fukuyama ◽  
Shigekazu Nagata ◽  
Rikiro Fukunaga
Keyword(s):  
Protein Synthesis ◽  
Cell Growth ◽  
Map Kinases ◽  
Insulin Injection ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Embryonic Fibroblasts ◽  
Cultured Fibroblasts ◽  
Eukaryotic Translation ◽  
Mitogen Activated Protein

ABSTRACT Mnk1 and Mnk2 are protein kinases that are directly phosphorylated and activated by extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein (MAP) kinases and implicated in the regulation of protein synthesis through their phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) at Ser209. To investigate their physiological functions, we generated mice lacking the Mnk1 or Mnk2 gene or both; the resulting KO mice were viable, fertile, and developed normally. In embryonic fibroblasts prepared from Mnk1-Mnk2 DKO mice, eIF4E was not detectably phosphorylated at Ser209, even when the ERK and/or p38 MAP kinases were activated. Analysis of embryonic fibroblasts from single KO mice revealed that Mnk1 is responsible for the inducible phosphorylation of eIF4E in response to MAP kinase activation, whereas Mnk2 mainly contributes to eIF4E's basal, constitutive phosphorylation. Lipopolysaccharide (LPS)- or insulin-induced upregulation of eIF4E phosphorylation in the spleen, liver, or skeletal muscle was abolished in Mnk1−/− mice, whereas the basal eIF4E phosphorylation levels were decreased in Mnk2−/− mice. In Mnk1-Mnk2 DKO mice, no phosphorylated eIF4E was detected in any tissue studied, even after LPS or insulin injection. However, neither general protein synthesis nor cap-dependent translation, as assayed by a bicistronic reporter assay system, was affected in Mnk-deficient embryonic fibroblasts, despite the absence of phosphorylated eIF4E. Thus, Mnk1 and Mnk2 are exclusive eIF4E kinases both in cultured fibroblasts and adult tissues, and they regulate inducible and constitutive eIF4E phosphorylation, respectively. These results strongly suggest that eIF4E phosphorylation at Ser209 is not essential for cell growth during development.

scholarly journals Light dependent activation of the GCN2 kinase under cold and salt stress is mediated by the photosynthetic status of the chloroplast

2019 ◽  
Author(s):  
Ansul Lokdarshi ◽  
Philip W. Morgan ◽  
Michelle Franks ◽  
Zoe Emert ◽  
Catherine Emanuel ◽  
...  
Keyword(s):  
Salt Stress ◽  
Reactive Oxygen ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Α Subunit ◽  
Eukaryotic Translation ◽  
The Status ◽  
Eukaryotic Translation Initiation

ABSTRACTRegulation of cytosolic mRNA translation is a key node for rapid adaptation to environmental stress conditions. In yeast and animals, phosphorylation of the α-subunit of eukaryotic translation initiation factor eIF2 is the most thoroughly characterized event in regulating global translation under stress. In plants, the GCN2 kinase (General Control Non-derepressible-2) is the only known kinase for eIF2α. GCN2 is activated under a variety of stresses including reactive oxygen species. Here we provide new evidence that the GCN2 kinase in Arabidopsis is also activated rapidly and in a light dependent manner by cold and salt treatments. These treatments alone did not repress global mRNA ribosome loading in a major way. The activation of GCN2 was attenuated by inhibitors of photosynthesis and antioxidants, suggesting that it is gated by the redox poise or the reactive oxygen status of the chloroplast. In keeping with these results, gcn2 mutant seedlings were more sensitive than wild type to both cold and salt in a root elongation assay. These data suggest that cold and salt stress may both affect the status of the cytosolic translation apparatus via the conserved GCN2-eIF2α module. The potential role of the GCN2 kinase pathway in the global repression of translation under abiotic stress will be discussed.

aubergineencodes aDrosophilapolar granule component required for pole cell formation and related to eIF2C

Development ◽  
2001 ◽  
Vol 128 (14) ◽  
pp. 2823-2832 ◽  
Author(s):  
Adam N. Harris ◽  
Paul M. Macdonald
Keyword(s):  
Polar Granule ◽  
Cell Formation ◽  
Posterior Pole ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Eukaryotic Translation ◽  
Pole Cell ◽  
Body Patterning ◽  
Pole Plasm

In Drosophila oocytes, activation of Oskar translation from a transcript localized to the posterior pole is an essential step in the organization of the pole plasm, specialized cytoplasm that contains germline and abdominal body patterning determinants. Oskar is a component of polar granules, large particles associated with the pole plasm and the germline precursor pole cells of the embryo. aubergine mutants fail to translate oskar mRNA efficiently and are thus defective in posterior body patterning and pole cell formation. We have found that Aubergine protein is related to eukaryotic translation initiation factor 2C and suggest how it may activate translation. In addition, we found that Aubergine was recruited to the posterior pole in a vas-dependent manner and is itself a polar granule component. Consistent with its presence in these structures, Aubergine is required for pole cell formation independently of its initial role in oskar translation. Unlike two other known polar granule components, Vasa and Oskar, Aubergine remains cytoplasmic after pole cell formation, suggesting that the roles of these proteins diverge during embryogenesis.

scholarly journals hnRNP K Binds a Core Polypyrimidine Element in the Eukaryotic Translation Initiation Factor 4E (eIF4E) Promoter, and Its Regulation of eIF4E Contributes to Neoplastic Transformation

2005 ◽  
Vol 25 (15) ◽  
pp. 6436-6453 ◽  
Author(s):  
Mary Lynch ◽  
Li Chen ◽  
Michael J. Ravitz ◽  
Sapna Mehtani ◽  
Kevin Korenblat ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Binding Protein ◽  
Neoplastic Transformation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Eukaryotic Translation Initiation Factor ◽  
Hnrnp K ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACT Translation initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a key role in regulation of cellular proliferation. Its effects on the m7GpppN mRNA cap are critical because overexpression of eIF4E transforms cells, and eIF4E function is rate-limiting for G1 passage. Although we identified eIF4E as a c-Myc target, little else is known about its transcriptional regulation. Previously, we described an element at position −25 (TTACCCCCCCTT) that was critical for eIF4E promoter function. Here we report that this sequence (named 4EBE, for eIF4E basal element) functions as a basal promoter element that binds hnRNP K. The 4EBE is sufficient to replace TATA sequences in a heterologous reporter construct. Interactions between 4EBE and upstream activator sites are position, distance, and sequence dependent. Using DNA affinity chromatography, we identified hnRNP K as a 4EBE-binding protein. Chromatin immunoprecipitation, siRNA interference, and hnRNP K overexpression demonstrate that hnRNP K can regulate eIF4E mRNA. Moreover, hnRNP K increased translation initiation, increased cell division, and promoted neoplastic transformation in an eIF4E-dependent manner. hnRNP K binds the TATA-binding protein, explaining how the 4EBE might replace TATA in the eIF4E promoter. hnRNP K is an unusually diverse regulator of multiple steps in growth regulation because it also directly regulates c-myc transcription, mRNA export, splicing, and translation initiation.

scholarly journals A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1

2018 ◽  
Vol 74 (3) ◽  
pp. 156-160 ◽  
Author(s):  
Yumi Matsui ◽  
Isao Yasumatsu ◽  
Ken-ichi Yoshida ◽  
Shin Iimura ◽  
Yutaka Ikeno ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Translation Initiation ◽  
Kinase Activity ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Structural Basis ◽  
Eukaryotic Translation ◽  
Mitogen Activated Protein ◽  
Eukaryotic Translation Initiation

Mitogen-activated protein kinase (MAPK)-interacting kinases 1 (Mnk1) and 2 (Mnk2) modulate translation initiation through the phosphorylation of eukaryotic translation initiation factor 4E, which promotes tumorigenesis. However, Mnk1 and Mnk2 are dispensable in normal cells, suggesting that the inhibition of Mnk1 and Mnk2 could be effective in cancer therapy. To provide a structural basis for Mnk1 inhibition, a novel Mnk1 inhibitor was discovered and the crystal structure of Mnk1 in complex with this inhibitor was determined. The crystal structure revealed that the inhibitor binds to the autoinhibited state of Mnk1, stabilizing the Mnk-specific DFD motif in the DFD-out conformation, thus preventing Mnk1 from switching to the active conformation and thereby inhibiting the kinase activity. These results provide a valuable platform for the structure-guided design of Mnk1 inhibitors.

scholarly journals Arginine Regulates TOR Signaling Pathway through SLC38A9 in Abalone Haliotis discus hannai

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2552
Author(s):  
Yue Liu ◽  
Haixia Yu ◽  
Yanlin Guo ◽  
Dong Huang ◽  
Jiahuan Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Mrna Levels ◽  
Tor Signaling ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation ◽  
Haliotis Discus ◽  
Solute Carrier ◽  
Abalone Haliotis Discus

Arginine plays an important role in the regulation of the target of the rapamycin (TOR) signaling pathway, and Solute Carrier Family 38 Member 9 (SLC38A9) was identified to participate in the amino acid-dependent activation of TOR in humans. However, the regulations of arginine on the TOR signaling pathway in abalone are still unclear. In this study, slc38a9 of abalone was cloned, and the slc38a9 was knocked down and overexpressed to explore its function in the regulation of the TOR signaling pathway. The results showed that knockdown of slc38a9 decreased the expression of tor, ribosomal s6 protein kinase (s6k) and eukaryotic translation initiation factor 4e (eif4e) and inhibited the activation of the TOR signaling pathway by arginine. Overexpression of slc38a9 up-regulated the expression of TOR-related genes. In addition, hemocytes of abalone were treated with 0, 0.2, 0.5, 1, 2 and 4 mmol/L of arginine, and abalones were fed diets with 1.17%, 1.68% and 3.43% of arginine, respectively, for 120 days. Supplementation of arginine (0.5–4 mmol/L) increased the expressions of slc38a9, tor, s6k and eif4e in hemocytes, and abalone fed with 1.68% of dietary arginine showed higher mRNA levels of slc38a9, tor, s6k and eif4e and phosphorylation levels of TOR, S6 and 4E-BP. In conclusion, the TOR signaling pathway of abalone can be regulated by arginine, and SLC38A9 plays an essential role in this regulation.

scholarly journals Structural basis for eIF2B inhibition in integrated stress response

Science ◽  
2019 ◽  
Vol 364 (6439) ◽  
pp. 495-499 ◽  
Author(s):  
Kazuhiro Kashiwagi ◽  
Takeshi Yokoyama ◽  
Madoka Nishimoto ◽  
Mari Takahashi ◽  
Ayako Sakamoto ◽  
...  
Keyword(s):  
Stress Response ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Structural Basis ◽  
Dependent Manner ◽  
Integrated Stress Response ◽  
Nucleotide Exchange ◽  
Electron Microscopic ◽  
Eukaryotic Translation ◽  
Initiation Factor 2

A core event in the integrated stress response, an adaptive pathway common to all eukaryotic cells in response to various stress stimuli, is the phosphorylation of eukaryotic translation initiation factor 2 (eIF2). Normally, unphosphorylated eIF2 transfers the methionylated initiator tRNA to the ribosome in a guanosine 5′-triphosphate–dependent manner. By contrast, phosphorylated eIF2 inhibits its specific guanine nucleotide exchange factor, eIF2B. To elucidate how the eIF2 phosphorylation status regulates the eIF2B activity, we determined cryo–electron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. These structures explain how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B.

scholarly journals The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer’s Disease

2021 ◽  
Vol 22 (6) ◽  
pp. 3136
Author(s):  
Jacques Hugon ◽  
Claire Paquet
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
P38 Map Kinase ◽  
Translation Initiation Factor ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mitogen Activated Protein

Neuropathological lesions in Alzheimer’s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR/P38/RIPK1 (PKR/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)/P38/MAP kinase-activated protein kinase 2 (MK2)/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR/MKK6/p38/MK2/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including Aβ accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.

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