RPL39L is an example of a recently evolved ribosomal protein paralog that shows highly specific tissue expression patterns and is upregulated in ESCs and HCC tumors

Wong, Queenie Wing-Lei; Li, Jia; Ng, Sheng Rong; Lim, Seng Gee; Yang, Henry; Vardy, Leah A.

doi:10.4161/rna.27427

Cited by 53 publications

(50 citation statements)

References 34 publications

(50 reference statements)

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“…Our results show that ribosome modularity is a dynamic, evolving process which seems to be involved in the evolution of species specific ribosomal proteins, the diversification of their sequences and functions and the creation of novel, species specific ribosomal proteins [57,58] leading to diverse phenotypic adaptations.…”

Section: Discussionmentioning

confidence: 99%

The Modular Adaptive Ribosome

et al. 2016

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The ribosome is an ancient machine, performing the same function across organisms. Although functionally unitary, recent experiments suggest specialized roles for some ribosomal proteins. Our central thesis is that ribosomal proteins function in a modular fashion to decode genetic information in a context dependent manner. We show through large data analyses that although many ribosomal proteins are essential with consistent effect on growth in different conditions in yeast and similar expression across cell and tissue types in mice and humans, some ribosomal proteins are used in an environment specific manner. The latter set of variable ribosomal proteins further function in a coordinated manner forming modules, which are adapted to different environmental cues in different organisms. We show that these environment specific modules of ribosomal proteins in yeast have differential genetic interactions with other pathways and their 5’UTRs show differential signatures of selection in yeast strains, presumably to facilitate adaptation. Similarly, we show that in higher metazoans such as mice and humans, different modules of ribosomal proteins are expressed in different cell types and tissues. A clear example is nervous tissue that uses a ribosomal protein module distinct from the rest of the tissues in both mice and humans. Our results suggest a novel stratification of ribosomal proteins that could have played a role in adaptation, presumably to optimize translation for adaptation to diverse ecological niches and tissue microenvironments.

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Section: Discussionmentioning

confidence: 99%

The Modular Adaptive Ribosome

et al. 2016

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“…“Specialized ribosomes”, tailored to preferentially translate specific mRNAs, or to have specific properties in particular environments are another possibility [6, 16, 17, 25, 46, 47, 50]. Support for this is found primarily in observations that ribosomal gene expression levels do vary between tissues [6, 7, 49, 51, 65, 66], and direct evidence of a regulatory role for individual RP proteins in selective mRNA translation and embryonic tissue patterning [6, 16, 43, 49, 50]. Furthermore, in Dictyostelium ribosome composition appears to shift with cell cycle [67, 68].…”

Section: Discussionmentioning

confidence: 99%

“…In support, reduction of Rpl38 in mice can alter the composition of Hox gene mRNAs translation and embryonic patterning, without reducing overall protein synthesis [6]. Furthermore, ribosomal gene mRNA expression exhibits significant variation across tissues [6, 46, 47, 49–51]. Such variation may result in differential ribosome production and activity.…”

Section: Introductionmentioning

confidence: 99%

Expression of ribosomopathy genes during Xenopus tropicalis embryogenesis

et al. 2016

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BackgroundBecause ribosomes are ubiquitously required for protein production, it was long assumed that any inherited defect in ribosome manufacture would be embryonically lethal. However, several human congenital diseases have been found to be associated with mutations in ribosome biogenesis factors. Surprisingly, despite the global requirement for ribosomes, these “ribosomopathies” are characterized by distinct and tissue specific phenotypes. The reasons for such tissue proclivity in ribosomopathies remain mysterious but may include differential expression of ribosome biogenesis factors in distinct tissues.MethodsHere we use in situ hybridization of labeled antisense mRNA probes and ultra high temporal resolution RNA-Seq data to examine and compare expression of 13 disease associated ribosome biogenesis factors at six key stages in Xenopus tropicalis development.ResultsRather than being ubiquitously expressed during development, mRNAs of all examined ribosome biogenesis factors were highly enriched in specific tissues, including the cranial neural crest and ventral blood islands. Interestingly, expression of ribosome biogenesis factors demonstrates clear differences in timing, transcript number and tissue localization.ConclusionRibosome biogenesis factor expression is more spatiotemporally regulated during embryonic development than previously expected and correlates closely with many of the common ribosomopathy phenotypes. Our findings provide information on the dynamic use of ribosome production machinery components during development and advance our understanding of their roles in disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-016-0138-5) contains supplementary material, which is available to authorized users.

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“…The top genes were analyzed, and knockdowns of Ribosomal protein L39 (RPL39) and Myeloid Leukemia Factor 2 (MLF2) were associated with a decrease in nitric oxide (NO) signaling (8), in particular inducible nitric oxide synthase (iNOS, NOS2). RPL39 is a structural protein of the ribosome at its polypeptide exit tunnel, a protein-sensitive channel that regulates translation through recognition of specific sequences (9,10). MLF2 is involved in chromosomal arm 12p aberrations associated with acute leukemias of lymphoid and myeloid lineage (11).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

Dávila‐González

Choi

Rosato

et al. 2018

Clinical Cancer Research

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Purpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC.Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition þ docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay.Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9.Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy.

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RPL39L is an example of a recently evolved ribosomal protein paralog that shows highly specific tissue expression patterns and is upregulated in ESCs and HCC tumors

Cited by 53 publications

References 34 publications

The Modular Adaptive Ribosome

The Modular Adaptive Ribosome

Expression of ribosomopathy genes during Xenopus tropicalis embryogenesis

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

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