Outline the role of ribosomes in protein synthesis
The nucleolus and ribosomes form part of the proteinsynthesizing machinery of the cell
Role of Ribosomes in Protein Synthesis - Video & …
Perturbations in the ER homeostasis contributes to the pathogenesis of several neurodegenerative diseases including prion diseases (). Accumulation of misfolded proteins in the ER activates the UPR to re-establish the balance between ER protein folding capacity and protein load resulting in cell survival. Chronic ER stress promotes cell death (). The mechanisms of transition between cell survival and cell death during UPR are still unclear. The conversion of PrPc to PrPSc is the hallmark of all TSEs (). While normal PrPc is an integral part of the cell playing an important role in neuronal homeostasis, PrPSc is indeed considered harmful for cell survival and misfolded forms of PrPSc triggers the ER stress signaling (Figure ; ). have shown that during transport through the ER, 10% of the native PrPc is naturally converted into misfolded form. This shows how prone they could be to get misfolded (). The importance of UPR in prolonged survival mechanisms was recently shown by where they demonstrated that mild activation of UPR through tunicamycin treatment prolonged the survival of prion infected mice. showed that UPR and ER associated degradation (ERAD) play an important role in the pathogenesis of prion diseases. Furthermore the absence of UPR and ERAD quality control impair cellular growth (). There are three mechanistically distinct branches of the UPR. Each branch begins with a specialized stress sensor located at the ER membrane: inositol requiring enzyme 1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6; Figure ; ). The first branch of the UPR relies on the dimerization of IRE1 and its autophosphorylation to initiate a signaling cascade mediated through the transcription factor X-box binding protein 1 (XBP-1) to upregulate a subset of the UPR related genes involved in the protein folding processes and the ERAD (). The second branch of the UPR is activated by the oligomerization of PERK protein that phosphorylates itself and the translation of initiation factor eIF2α. That in turn inactivating eIF2α and result in the translational shutdown. The third UPR pathway is initiated by the ATF6 following cleavage in the golgi apparatus, which increases the expression of the glucose regulated proteins (grp78) and the XBP-1 transcription factor (). To date most extensive work has been carried out on the IRE1 and PERK pathway in prion diseases and some minor work has been done on ATF6 pathway of the UPR.
The main purpose of the PERK pathway signaling cascade is to relieve the ER stress by reducing the amount of proteins entering the ER (). have shown that PERK pathway took an active part during prion infection of the wild type mice and all the hippocampi of prion-infected wild type mice and those overexpressing PrPc had activated PERK branch of the UPR. As PrPSc levels rise in PrPc overexpressing mice infected with prions, there is global translational repression of the protein synthesis via phosphorylation of the eIF2α (eIF2α-P). The general decline in several synaptic proteins levels during infection was proposed to be a key trigger for neurodegeneration (). Similarly, DNA damage inducible protein 34 (GADD34) overexpressing mice model or chemical inhibition of the PERK by using PERK inhibitor GSK2606414 ameliorated neurodegeneration in prion-infected mice. On the other hand activation of the PERK pathway using salubrinal worsened prion associated neurotoxic events (; ). However, since the PERK pathway can reduce the protein levels without altering the mRNA levels, ER stress induced translational repression of the PRNP remains a potential mechanism for the preclinical reduction in the PrPc levels observed during prion diseases (). have shown that Snord3A is a consistent biomarker of prion disease in a mice model and Snord3A is directly correlated with the ATF6 levels in brain homogenates of prion infected mice. These studies highlight two critical points: (1) PERK activation leads to phosphorylation of eIF2α and subsequent inactivation of eIF2α occurs downstream to PrPSc replication in the prion diseased mice; and (2) reversing the translational repression of the synaptic proteins is a valid therapeutic strategy for prion disease.
What Is the Role of DNA in Protein Synthesis
We examined the production of NF-κB factors, p50 andp52, which were associated with Bcl-3 by western blot analysis toinvestigate the molecular mechanism through which excess Bcl-3inhibited the Tax-induced NF-κB activity. The production of p50 waselevated significantly in the presence of exogenous Bcl-3 in MT2cells, whereas its precursor, p105, was not significantly changed(). By contrast, the p100and p52 proteins slightly increased in the Bcl-3-transfected MT2cells. Cyclin D1 expression was weakly inhibited in MT2 cells,which expressed high levels of exogenous Bcl-3. The redundant Bcl-3almost did not influence the p65 expression (). These data indicate thatexcessive levels of Bcl-3, while stabilizing p50, may play anegative role in the regulation of cyclin D1.
Whole cell lysates were extracted from cellssuspended in radio immune precipitation buffer supplemented with 1mM PMSF (Beyotime, China). The cytoplasmic and nuclear extractswere obtained using the Cytoplasmic and Nuclear Extract kit(Beyotime) according to the manufacturer’s instructions. Thelysates were resolved by electrophoresis on polyacrylamide gelscontaining 0.1% SDS (SDS-PAGE) and then transferred to thenitrocellulose membranes. The blots were incubated with theappropriate primary antibody diluted by TBST and then exposed tothe appropriate second antibody conjugated with horseradishperoxidase after being washed with TBST. The bands on the membranewere visualized and captured using the ECL reagent (Beyotime) andX-ray films (Kodak, USA). The pixel densities of proteins werequantitated using ImageJ 1.44 software (National Institute ofHealth). Graphs represent the pixel density for different proteinsnormalized to β-actin.
To understand the role of DNA in protein synthesis, ..
All major protein misfolding diseases, including AD, PD, Huntington’s disease (HD) and prion diseases have harmful effects on humans and animals due to lack of effective therapeutic strategies and presymptomatic diagnostic tools. Thus there is a need of novel therapeutic intervention strategies to control these diseases. Here in this review article, we will focus on the role of UPR and MAPK signaling cascades in neurodegenerative diseases with special focus on prion diseases.
Figure 1. Schematic presentation of the prion protein scrapie (PrPSc) accumulation and subsequent endoplasmic reticulum (ER) stress mediated activation of the iinositol requiring enzyme 1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6). PERK pathway, through PERK phosphorylation and translation of initiation factor 2 (eIF2α) phosphorylation, inactivates eIF2α and attenuates translation via activating transcription factor 4 (ATF4), which ultimately results in activation of C/EBP homologous protein (CHOP) and pro-apototic, growth arrest and DNA damage-inducible protein 34 (GADD34) and ER oxido-reductin 1 (ER01) genes. IRE1 pathway activates apoptotic signaling via BCL2-associated X protein (BAX) and BCL2 antagonist/killer (BAK). TNF receptor associated factor 2 (TRAF2), results in the activation of IkB kinase (IKK) and apoptosis signal regulating kinase (ASK), IKK through inhibitory kappa B (IkB) activates nuclear factor of kappa B (NFkB) and ultimately apoptotic signaling occurs. On the other hand ASK phosphorylation results in the activation of c-Jun NH2-terminal protein kinase (JNK) and p38 pathway of mitogen activated protein kinase (MAPK) pathways. Phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) results in death via conjunction with JNK. Activating Transcription factor 6 (ATF6) pathway via site 1 and site 2 proteases (S1P and S2P) activates transcription factor p50 in nucleus.
What is the role of mRNA in protein synthesis? - …
What Are the Roles of Ribosomes in Protein Synthesis?
The transcription of mRNA from DNA which in turn leads to protein synthesis ..
Protein Synthesis; Role of Golgi ..
This genetic information is found in the nucleus, though protein synthesis ..
Role of Ribosomes in Protein Synthesis ..
The function of the Golgi Apparatus and Endoplasmic reticulum in protein synthesis ..
The Role of DNA in Protein and Enzyme Synthesis - …
Halliday, M., Radford, H., Sekine, Y., Moreno, J., Verity, N., le Quesne, J., et al. (2015). Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. 6:e1672. doi: 10.1038/cddis.2015.49
Role of the Nucleus and Ribosomes in Protein Synthesis
There are many evidences suggesting the role of misfolded prion proteins in the initiation of ER stress mediated IRE1, PERK and ATF6 pathways. The adaptive response to ER stress is called UPR which is aimed at correcting overall protein processing in order to reduce the accumulation of misfolded proteins and restore the normal cellular functions. If ER stress is too severe or if the adaptive response fails to compensate the ER stress produced then synaptic dysfunction and apoptosis occurs. There are clearly strong links between the UPR signaling cascades and MAPK pathways in all major protein misfolding disease including prion diseases. In some cases the UPR signaling results in the activation of MAPK pathways so the UPR act as a trigger for the MAPKs; in addition, there are several other pathways where many interaction points allow cross talk between these pathways. Accumulation of misfolded proteins initiates the UPR and promote the activation of ERK1/2 under the effect of IRE1 pathway on one hand and JNK activation through IRE1-TNF receptor associated factor 2 (TRAF2)-ASK signaling or due to the Ca2+ dysregulation in response to ER stress. In addition the modulation of UPR can occur through the activation of MAPK p38 and subsequently phosphorylating CHOP and ATF6 proteins. Generally the ERK1/2 activation is considered to promote cell survival signaling. In contrast the JNK and p38 pathway signaling is considered pro-apoptotic. However, several exceptions do exist; for example, JNK signaling under the influence of IRE1 pathway promotes c-Jun activity and the expression of pro-survival protein Adapt78. Additionally ERK1/2 signaling cascade protect the cell against ER stress stimulus (such as in prion protein infected N2a and SN56 cell line and melanoma cells). But there are several cases where ERK1/2 can be apoptotic (such as colorectal melanoma cell line, HCT116 cell line, or the neuroblastoma cell line SH-SY5Y). The mechanism of MAPK signaling requires further molecular research to determine whether MAPK-dependent signaling can promote cell proliferation, survival or cell death. Scientists are agreed on the analogy with the other investigations that the response to ER stress could prove crucial in reflecting the differences in the duration of signaling, magnitude of signaling, relationship with other signaling pathways and to some extent cell type-specific expression of MAPK cascades. Although there are still several challenges in understanding the role of MAPK signaling and ER stress in prion diseases there are cases where there are indications that therapeutics to manipulate both UPR and MAPK signaling could be advantageous. To date studies on prion disease models or models none has focused on inhibiting UPR and MAPK pathways simultaneously. work on mice model of prion disease focused on the role of PERK pathway or Orsi et al.’s work on IRE1α pathway have clearly shown the importance of PERK and IRE1-XBP1 pathways in prion misfolding diseases. They have shown that PERK inhibition and XBP1 overexpression resulted in the alleviation of ER stress (; , ). On the other hand Thellung et al.’s work on an model of prion diseases has shown the prosurvival effects of p38 MAPK inhibition in SH-SY5Y cells. This neuroprotective effect of SB203580 and PD169316 (p38 Inhibitors) reversed caspase mediated cell death in prion disease cell model (). Similarly pJNK has been found to be upregulated both in and model of prion diseases (; ). ERK1/2 phosphorylation is yet to be understood in prion diseases as and shown pERK upregulation in prion diseases, and this upregulation was neuroprotective.
Role of Ribosomes in Protein Synthesis | Genetics
Figure 3. Schematic presentation of cell death mechanisms in prion disease. The cellular PrP (PrPc) is found on the cell membrane, upon change from PrPc to prion protein scrapie (PrPSc), it is internalized by cell membrane bound receptors and transported to ER for folding and processing. The accumulation of misfolded PrPSc in ER leads to perturbations in calcium (Ca2+) homeostasis, which ultimately leads to pro-apoptic BCL-2 associated death (BAD) translocation into mitochondria and release of cyctochrome-c and apoptotic activating factors from mitochondria, triggering caspase-dependent apoptotic signaling. Dysregulated Ca2+ homeostasis results in reduced ATP production in mitochondria leading to reactive oxygen species (ROS) production. Under caspase-dependent apoptotic surge caspe-3 is degraded via p53 and p38 transcription factors leading to DNA fragmentation in nucleus of the cell (, ,; ).
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