scholarly journals Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?

2021 ◽  
Vol 23 (1) ◽  
pp. 48
Author(s):  
Yong Weon Yi ◽  
Kyu Sic You ◽  
Jeong-Soo Park ◽  
Seok-Geun Lee ◽  
Yeon-Sun Seong
Keyword(s):  
Ribosomal Protein ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Ribosomal Subunit ◽  
Surrogate Marker ◽  
Mrna Translation ◽  
Ribosomal Protein S6 ◽  
History Of ◽  
Mtorc1 Pathway ◽  
Cancer Types

Ribosomal protein S6 (RPS6) is a component of the 40S small ribosomal subunit and participates in the control of mRNA translation. Additionally, phospho (p)-RPS6 has been recognized as a surrogate marker for the activated PI3K/AKT/mTORC1 pathway, which occurs in many cancer types. However, downstream mechanisms regulated by RPS6 or p-RPS remains elusive, and the therapeutic implication of RPS6 is underappreciated despite an approximately half a century history of research on this protein. In addition, substantial evidence from RPS6 knockdown experiments suggests the potential role of RPS6 in maintaining cancer cell proliferation. This motivates us to investigate the current knowledge of RPS6 functions in cancer. In this review article, we reviewed the current information about the transcriptional regulation, upstream regulators, and extra-ribosomal roles of RPS6, with a focus on its involvement in cancer. We also discussed the therapeutic potential of RPS6 in cancer.

scholarly journals Molecular mechanisms for the control of translation by insulin

1997 ◽  
Vol 328 (2) ◽  
pp. 329-341 ◽  
Author(s):  
G. Christopher PROUD ◽  
M. Richard DENTON
Keyword(s):  
Ribosomal Protein ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Chain Elongation ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Translation Factors ◽  
Specific Mrnas

Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5ʹ-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5ʹ-untranslated regions (5ʹ-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5ʹ-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general activation of translation and to the selective regulation of specific mRNAs.

Expression of Ribosomal Protein S6 (R6SP) and Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (EIF4EBP1) Is Correlated in Acute Myelogenous Leukemia (AML) and Is Highly Prognostic, Especially in NPM1 and FLT3 Wildtype Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2369-2369
Author(s):  
Steven M. Kornblau ◽  
Chenyue W Hu ◽  
Yihua Qiu ◽  
Suk Young Yoo ◽  
Rebecca A Murray ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Ribosomal Subunit ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Npm1 Mutation ◽  
Eukaryotic Translation ◽  
Ribosomal Protein S6 ◽  
40S Ribosomal Subunit ◽  
Eukaryotic Translation Initiation

Abstract Background. Conceptually mRNA processing and ribosomal regulation should interact as both affect mRNA translation and protein production. We studied protein expression and functional relationships between proteins in AML using a custom made reverse phase protein array (RPPA), probed with 231 strictly validated antibodies. We found a relationship between expression of Ribosomal Protein S6 (HUGO name R6SP, a.k.a. S6RP) and Eukaryotic Translation Initiation Factor 4EBinding Protein 1, (HUGO name EIF4EBP1). R6SP, a 40S ribosomal subunit component, activated by phosphorylation, regulates cell growth via selective mRNA translation. EIF4EBP1 interacts with eIF4E to recruit the 40S ribosomal subunit, thereby affecting ribosomal assembly. When phosphorylated, in response to cellular signaling, it releases eIF4E allowing transcription. Methods. Our RPPA has protein from leukemia enriched cells from 511 newly diagnosed AML patients and was probed with 231 strictly validated antibodies, including antibodies against total RPS6 and forms phosphorylated on S235-236 and S240-244, and against total EIF4EBP1 and forms phosphorylated on T37 & 46, T70 and S65. Expression was compared to normal bone marrow derived CD34+ cells. Interaction networks with the other 224 proteins were generated from the RPPA data using glasso and supplemented by the literature of known interactions. Results. A heatmap of expression of the 3 R6SP and 4 PA2 forms was generated and hierarchical k-and means clustering performed (Fig A). Using the “Prototype Clustering ”method an optimal division into four clusters (Fig B) was determined. This includes an “All-Off” state (18%), a state characterized by weak activation of RPS6 alone (RP-Only, 36%) activation of only EIF4EBP1 (EIF4EBP1-Only, 26%) and a group where both were on simultaneously (Both-On). The RPS6 interactome (Fig B) showed the expected positive correlation with mTOR, and P70 (Hugo RPS6KB1) and a previously unknown, but very strong, negative correlation with transcription factor ZNF296. The EIF4EBP1 interactome showed the expected strong positive correlation with many signal transduction pathways (MAP2K1, MAPK14) and proliferation related proteins (pRB, EIF2AK, EIF2S1, FOXO3) and negative correlation with several transcription factors (GATA3, SPI1, CREB). Cluster membership was unassociated with most clinical features including cytogenetics, FLT3 , RAS and NPM1 mutation, excluding gender (more F in All-Off, more M in Both-On, p=0.01). EIF4EBP1 and Both-On had higher WBC (p=0.0001) and % marrow (p=0.0001) and blood blasts (0.0007) and lower platelet counts (p=0.025). Response rates did not differ, although fewer All-Off were primary refractory. Relapse was more common in EIF4EBP1-Only and Both-On clusters. Overall survival (OS) and remission duration (RemDur) (Fig C) of the EIF4EBP1-Only and Both-On clusters was inferior to that of the All-Off and RP-Only clusters (OS median 41 & 45 vs. 52 &63,p=0.06, RemDur 39 & 27 weeks vs. 63 & 53, p=0.008) but this was restricted to Intermediate cytogenetics cases (Fig C “IntCyto” OS 49 & 55 weeks vs. 107& 79 p=0.01, RemDur 37 & 35 weeks vs. 89 & 53 , p = 0.005) that were FLT3 mutation ((Fig C “FLT3-WT” OS p=0.006, RemDur p0.007) and NPM1 mutation negative (Fig C “NPM1-WT”, OS p=0.006, RemDur p=0.001). Conclusions. Activation of EIF4EBP1, with or without RPS6 activation is prognostically adverse in AML, particularly in intermediate cytogenetic cases with wildtype FLT3 and NPM1. This is associated with increased proliferation. Therapy directed against EIF4EBP1 activity, e.g. that block it's phosphorylation, may have utility in the ~46% of cases of AML that demonstrate high levels of EIF4EBP1 phosphorylation, especially in FLT3/NPM1 wildtype cases. Many agents that inhibit signal transduction pathways are in clinical development, analyzing them for the ability to inhibition the activation of EIF4EBP1 might identify clinically useful molecules. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals GenusTinospora: Ethnopharmacology, Phytochemistry, and Pharmacology

2016 ◽  
Vol 2016 ◽  
pp. 1-32 ◽  
Author(s):  
Sensen Chi ◽  
Gaimei She ◽  
Dan Han ◽  
Weihua Wang ◽  
Zhao Liu ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Current Knowledge ◽  
Biological Activities ◽  
Modern Medicine ◽  
Convincing Evidence ◽  
Extensive Literature ◽  
Traditional Medicines ◽  
Digestive Disorder ◽  
Indigenous Groups ◽  
History Of

The genusTinosporaincludes 34 species, in which several herbs were used as traditional medicines by indigenous groups throughout the tropical and subtropical parts of Asia, Africa, and Australia. The extensive literature survey revealedTinosporaspecies to be a group of important medicinal plants used for the ethnomedical treatment of colds, headaches, pharyngitis, fever, diarrhea, oral ulcer, diabetes, digestive disorder, and rheumatoid arthritis. Indian ethnopharmacological data points to the therapeutic potential of theT.cordifoliafor the treatment of diabetic conditions. WhileTinosporaspecies are confusing in individual ingredients and their mechanisms of action, the ethnopharmacological history of those plants indicated that they exhibit antidiabetic, antioxidation, antitumor, anti-inflammation, antimicrobial, antiosteoporosis, and immunostimulation activities. While the clinical applications in modern medicine are lacking convincing evidence and support, this review is aimed at summarizing the current knowledge of the traditional uses, phytochemistry, biological activities, and toxicities of the genusTinosporato reveal its therapeutic potentials and gaps, offering opportunities for future researches.

scholarly journals The Р60-S6K1 isoform of ribosomal protein S6 kinase 1 is a product of alternative mRNA translation

2018 ◽  
Vol 90 (4) ◽  
pp. 25-35 ◽  
Author(s):  
I. V. Zaiets ◽  
◽  
A. S. Sivchenko ◽  
A. I. Khoruzhenko ◽  
L. O. Savinska ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Mrna Translation ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase

Glucose exerts a permissive effect on the regulation of the initiation factor 4E binding protein 4E-BP1

2001 ◽  
Vol 358 (2) ◽  
pp. 497-503 ◽  
Author(s):  
Jigna PATEL ◽  
Xuemin WANG ◽  
Christopher G. PROUD
Keyword(s):  
Amino Acids ◽  
Ribosomal Protein ◽  
Binding Protein ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Ribosomal Protein S6 ◽  
P70 S6k ◽  
Effect Of Glucose

The eukaryotic initiation factor 4E (eIF4E) binding protein (4E-BP1) interacts directly with eIF4E and prevents it from forming initiation factor (eIF4F) complexes required for the initiation of cap-dependent mRNA translation. Insulin and other agents induce the phosphorylation of 4E-BP1 at multiple sites, resulting in its release from eIF4E, and this involves signalling through the mammalian target of rapamycin (mTOR). Here we show that d-glucose promotes the ability of insulin to bring about the phosphorylation of 4E-BP1 and the formation of eIF4F complexes. This appears to involve facilitation of the phosphorylation of at least three phosphorylation sites on 4E-BP1, i.e. Thr-36, Thr-45 and Thr-69. Non-metabolizable glucose analogues cannot substitute for d-glucose, but other hexoses can. This suggests that a product of hexose metabolism mediates the permissive effect of glucose. The effect of glucose was concentration-dependent within the range 1–5mM. In contrast with the situation for 4E-BP1, glucose does not allow full activation of the 70kDa ribosomal protein S6 kinase (p70 S6k; another target of mTOR signalling) or phosphorylation, in vivo, of its substrate, ribosomal protein S6. Taken together with earlier data showing that amino acids regulate 4E-BP1 and p70 S6k, the present findings show that 4E-BP1 in particular is regulated in response to the availability of both amino acids and sugars.

scholarly journals Phosphorylation of Ribosomal Protein S6 differentially affects mRNA translation based on ORF length

2021 ◽  
Author(s):  
Jonathan Bohlen ◽  
Aurelio A. Teleman
Keyword(s):  
Ribosomal Protein ◽  
Mrna Translation ◽  
Translation Efficiency ◽  
Post Translational Modification ◽  
Coding Sequences ◽  
Functional Consequence ◽  
Ribosomal Protein S6 ◽  
Dynamic View ◽  
Ribosome Footprinting ◽  
Rps6 Phosphorylation

ABSTRACTPhosphorylation of Ribosomal Protein S6 (RPS6) was the first post-translational modification of the ribosome to be identified and is a commonly-used readout for mTORC1 activity. Although the cellular and organismal functions of RPS6 phosphorylation are known, its molecular consequences on translation are less well understood. Here we use selective ribosome footprinting to analyze the location of ribosomes containing phosphorylated RPS6 on endogenous mRNAs in cells. We find that RPS6 becomes progressively dephosphorylated on ribosomes as they translate an mRNA. As a consequence, average RPS6 phosphorylation is higher on mRNAs with short coding sequences (CDSs) compared to mRNAs with long CDSs. In particular, ribosomes translating on the endoplasmic reticulum are more rapidly dephosphorylated than cytosolic ribosomes. Loss of RPS6 phosphorylation causes a correspondingly larger drop in translation efficiency of mRNAs with short CDSs than long CDSs. Interestingly, mRNAs with 5’ TOP motifs are translated well also in the absence of RPS6 phosphorylation despite short CDS lengths, suggesting they are translated via a different mode. In sum this provides a dynamic view of RPS6 phosphorylation on ribosomes as they translate mRNAs in different subcellular localizations and the functional consequence on translation.

scholarly journals Lutropin increases phosphorylation of a 33 000-dalton ribosomal protein in rat tumour Leydig cells

1982 ◽  
Vol 204 (3) ◽  
pp. 809-815 ◽  
Author(s):  
G H Bakker ◽  
J W Hoogerbrugge ◽  
F F G Rommerts ◽  
H J van der Molen
Keyword(s):  
Protein Synthesis ◽  
Luteinizing Hormone ◽  
Subcellular Localization ◽  
Ribosomal Protein ◽  
Molecular Mass ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Ribosomal Subunit ◽  
Ribosomal Protein S6 ◽  
Leydig Cell Tumour

Addition of lutropin (luteinizing hormone, ‘LH’) and 3-isobutyl-1-methylxanthine to tumour Leydig cells stimulated phosphorylation of five proteins, of 17 000, 22 000, 24 000, 33 000 and 57 000 Da. Phosphorylation of these proteins coincided with increased pregnenolone production. Phosphorylation of a 33 000-Da protein was lutropin-dependent in Leydig cells isolated from a Leydig-cell tumour, from immature testes or from mature testes. In tumour Leydig cells this protein was present in the small ribosomal subunit. Incubation of tumour Leydig cells with either cycloheximide or puromycin inhibited both basal and lutropin-dependent pregnenolone production, by approx. 90% and 98% respectively. In contrast, basal pregnenolone production in Leydig cells from immature and mature testes was insensitive to cycloheximide or puromycin. Cycloheximide or puromycin increased phosphorylation of the 33 000-Da phosphoprotein by approx. 130% and 80% respectively (effect of lutropin/3-isobutyl-1-methylxanthine on phosphorylation: 100%). The molecular mass, the subcellular localization and the sensitivity to phosphorylation in the presence of inhibitors of protein synthesis indicate that the 33 000-Da protein could be similar to ribosomal protein S6.

p70 Ribosomal protein S6 kinase (Rps6kb1): an update

2014 ◽  
Vol 67 (12) ◽  
pp. 1019-1025 ◽  
Author(s):  
Farnaz Bahrami-B ◽  
Parvin Ataie-Kachoie ◽  
Mohammad H Pourgholami ◽  
David L Morris
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Ribosomal Subunit ◽  
Mtor Inhibitors ◽  
Therapeutic Index ◽  
Drug Induced ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase

The Rps6kb1 gene encodes the 70 kDa ribosomal protein S6 kinase (p70S6K), which is a serine/threonine kinase regulated by phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. p70S6K plays a crucial role in controlling cell cycle, growth and survival. The PI3K/mTOR signalling pathway is one of the major mechanisms for controlling cell survival, proliferation and metabolism and is the central regulator of translation of some components of protein synthesis system. Upon activation, this kinase phosphorylates S6 protein of ribosomal subunit 40S resulting in selective translation of unique family of mRNAs that contain oligopyrimidine tract on 5’ transcriptional site (5′TOP). 5′TOP mRNAs are coding the components of translational apparatus including ribosomal proteins and elongation factors. Due to the role of p70S6K in protein synthesis and also its involvement in a variety of human diseases ranging from diabetes and obesity to cancer, p70S6K is now being considered as a new therapeutic target for drug development. Furthermore, p70S6K acts as a biomarker for response to immunosuppressant as well as anticancer effects of inhibitors of the mTOR. Because of the narrow therapeutic index of mTOR inhibitors, drug monitoring is essential, and this is usually done by measuring blood drug levels, therapeutic response and drug-induced adverse effects. Recent studies have suggested that plasma p70S6K is a reliable index for the monitoring of patient response to mTOR inhibitors. Therefore, a better understanding of p70S6K and its role in various pathological conditions could enable the development of strategies to aid diagnosis, prognosis and treatment schedules.

scholarly journals YbeY, éminence grise of ribosome biogenesis

2021 ◽  
Author(s):  
Zhen Liao ◽  
Cédric Schelcher ◽  
Alexandre Smirnov
Keyword(s):  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Current Knowledge ◽  
Critical Role ◽  
Ribosomal Subunit ◽  
Biochemical Data ◽  
Small Protein ◽  
Cellular Physiology ◽  
Bacterial Origin ◽  
Bacterial Type

YbeY is an ultraconserved small protein belonging to the unique heritage shared by most existing bacteria and eukaryotic organelles of bacterial origin, mitochondria and chloroplasts. Studied in more than a dozen of evolutionarily distant species, YbeY is invariably critical for cellular physiology. However, the exact mechanisms by which it exerts such penetrating influence are not completely understood. In this review, we attempt a transversal analysis of the current knowledge about YbeY, based on genetic, structural, and biochemical data from a wide variety of models. We propose that YbeY, in association with the ribosomal protein uS11 and the assembly GTPase Era, plays a critical role in the biogenesis of the small ribosomal subunit, and more specifically its platform region, in diverse genetic systems of bacterial type.

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