p70 Ribosomal protein S6 kinase (<i>Rps6kb1</i>): an update

Bahrami-B, Farnaz; Ataie-Kachoie, Parvin; Pourgholami, Mohammad H.; Morris, David L.

doi:10.1136/jclinpath-2014-202560

Cited by 65 publications

(58 citation statements)

References 107 publications

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“…This included amplification and overexpression of the oncogene RAD51C , which is commonly amplified in breast cancer and may play a drive role in this one patient with multiple myeloma 53 . Two additional patients had >6 copies and outlier overexpression of RPS6KB1 , encoding the 70 kDa ribosomal protein S6 kinase (p70S6K), a crucial regulator of cell cycle, growth and survival in the PI3K/mTOR pathways ( Figure S7C ) 54 . These observations raise questions regarding the impact of rare SVs in deregulating potential drivers, and their contribution to multiple myeloma biology overall.…”

Section: Resultsmentioning

confidence: 99%

Revealing the impact of recurrent and rare structural variants in multiple myeloma

Rustad

Yellapantula

Glodzik

et al. 2019

Preprint

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53The landscape of structural variants (SVs) in multiple myeloma remains poorly 54 understood. Here, we performed comprehensive classification and analysis of SVs in 55 multiple myeloma, interrogating a large cohort of 762 patients with whole genome and 56 RNA sequencing. We identified 100 SV hotspots involving 31 new candidate driver 57 genes, including drug targets BCMA (TNFRSF17) and SLAMF7. Complex SVs, 58 including chromothripsis and templated insertions, were present in 61 % of patients and 59 frequently resulted in the simultaneous acquisition of multiple drivers. After accounting 60 for all recurrent events, 63 % of SVs remained unexplained. Intriguingly, these rare SVs 61were associated with up to 7-fold enrichment for outlier gene expression, indicating that 62 many rare driver SVs remain unrecognized and are likely important in the biology of 63 individual tumors. 64 65 whole chromosome gains later in tumor evolution 13,20 . The second category is made up of 89 all other recurrent copy number alterations (CNAs), one or more of which are present in 90 virtually all patients 19,20 . Among these, gain of chromosome 1q21 often occurs early in 91 tumor evolution, while loss of tumor suppressor genes tends occur later 20-23 . The 92 structural basis of these established drivers remains poorly understood, and there is a lack 93 of data about the role of SVs beyond the most recurrent aberrations. 94We recently reported the first comprehensive SV characterization using WGS of 95 sequential samples from 30 multiple myeloma patients 20 . Despite the small sample set, 96SVs emerged as key drivers during all evolutionary phases of disease, and we identified a 97 high prevalence of three main classes of complex SVs: chromothripsis, templated 98 insertions and chromoplexy 20 . In chromothripsis, chromosomal shattering and random 99 rejoining results in a pattern of tens to hundreds of breakpoints with oscillating copy 100 number across one or more chromosomes 24 . Templated insertions are characterized by 101 focal gains bounded by translocations, resulting in concatenation of amplified segments 102 from two or more chromosomes into a continuous stretch of DNA, which is inserted back 103 into any of the involved chromosomes 2,20 . Chromoplexy similarly connects segments 104 from multiple chromosomes, but the local footprint is characterized by copy number 105 loss 25 . Importantly, complex SVs represent large-scale genomic alterations acquired by 106 the cancer cell at a single point in time, potentially driving subsequent tumor evolution. 107Here, we present the first comprehensive study of SVs in a large series of 762 108 multiple myeloma patients. We show that recurrent and rare SVs are critical in shaping 109 the genomic landscape of multiple myeloma, including complex events simultaneously 110 causing multiple drivers. 111 6 112 Results 113 Genome-wide landscape of structural variation in multiple myeloma 114To define the landscape of simple and complex SVs in multiple myeloma, we 115 investigated 762 newly di...

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Section: Resultsmentioning

confidence: 99%

Revealing the impact of recurrent and rare structural variants in multiple myeloma

Rustad

Yellapantula

Glodzik

et al. 2019

Preprint

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“…The inhibition of mTOR blocks p70 ribosomal S6 kinase (S6K), which then leads to the inhibition of stem cell differentiation via telomerase activity reduction . S6K has been well known in regulating the cell cycle, growth, and survival .…”

Section: Discussionmentioning

confidence: 99%

Neuronal Stem Cell and Drug Interactions: A Systematic Review and Meta-Analysis: Concise Review

Ikhsan

Palumbo

Rose

et al. 2019

Stem Cells Translational Medicine

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Stem cell therapy is a promising treatment option for neurodegenerative diseases that mostly affect geriatric patients who often suffer from comorbidities requiring multiple medications. However, not much is known about the interactions between stem cells and drugs. Here, we focus on the potential interactions between drugs used to treat the comorbidities or sequelae of neurodegenerative diseases and neuronal stem cells to reveal potential effects on drug safety and efficacy. To determine the potential effects of drugs frequently used in geriatric patients (analgesic, antibiotic, antidepressant, antidiabetic, antihyperlipidemic, and antihypertensive drugs) on neuronal stem cell differentiation and proliferation, we systematically searched PubMed to identify nonreview articles published in English in peer‐reviewed journals between January 1, 1991, and June 7, 2018. We identified 5,954 publications, of which 214 were included. Only 62 publications provided the complete data sets required for meta‐analysis. We found that antidepressants stimulated neuronal stem cell proliferation but not differentiation under physiologic conditions and increased the proliferation of stem cells in the context of stress. Several other potential interactions were identified, but the limited number of available data sets precludes robust conclusions. Although available data were in most cases insufficient to perform robust meta‐analysis, a clear interaction between antidepressants and neuronal stem cells was identified. We reveal other potential interactions requiring further experimental investigation. We recommend that future research addresses such interactions and investigates the best combination of pharmacological interventions and neuronal stem cell treatments for more efficient and safer patient care. Stem Cells Translational Medicine 2019;8:1202–1211

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“…Mammalian TORC1 promotes cell growth and proliferation, a reason whereby its activity and/or levels are frequently increased in human tumors [13]. Two main targets of mTORC1 are p70S6 kinase 1 (also S6K1) and eukaryotic initiation factor 4E-binding protein 1 (eIF4), both regulating mRNA translation initiation and progression, thus the rate of protein synthesis [12, 14]. The active form of mTORC1 resides at the lysosomes where it directly prevents autophagy and controls lysosome function [15].…”

Section: Introductionmentioning

confidence: 99%

MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability

et al. 2017

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BackgroundMany tumor-related factors have shown the ability to affect metabolic pathways by paving the way for cancer-specific metabolic features. Here, we investigate the regulation of mTORC1 by MDM4, a p53-inhibitor with oncogenic or anti-survival activities depending on cell growth conditions.MethodMDM4-mTOR relationship was analysed through experiments of overexpression or silencing of endogenous proteins in cell culture and using purified proteins in vitro. Data were further confirmed in vivo using a transgenic mouse model overexpressing MDM4. Additionally, the Cancer Genome Atlas (TCGA) database (N = 356) was adopted to analyze the correlation between MDM4 and mTOR levels and 3D cultures were used to analyse the p53-independent activity of MDM4.ResultsFollowing nutrient deprivation, MDM4 impairs mTORC1 activity by binding and inhibiting the kinase mTOR, and contributing to maintain the cytosolic inactive pool of mTORC1. This function is independent of p53. Inhibition of mTORC1 by MDM4 results in reduced phosphorylation of the mTOR downstream target p70S6K1 both in vitro and in vivo in a MDM4-transgenic mouse. Consistently, MDM4 reduces cell size and proliferation, two features controlled by p70S6K1, and, importantly, inhibits mTORC1-mediated mammosphere formation. Noteworthy, MDM4 transcript levels are significantly reduced in breast tumors characterized by high mTOR levels.ConclusionOverall, these data identify MDM4 as a nutrient-sensor able to inhibit mTORC1 and highlight its metabolism-related tumor-suppressing function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0626-7) contains supplementary material, which is available to authorized users.

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p70 Ribosomal protein S6 kinase (Rps6kb1): an update

Cited by 65 publications

References 107 publications

Revealing the impact of recurrent and rare structural variants in multiple myeloma

Revealing the impact of recurrent and rare structural variants in multiple myeloma

Neuronal Stem Cell and Drug Interactions: A Systematic Review and Meta-Analysis: Concise Review

MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability

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