scholarly journals ACKR3 induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis

2021 ◽  
Author(s):  
Xian Jun Qu ◽  
Juan Yang ◽  
Ya-Nan Li ◽  
Ting Pan ◽  
Rong-Rong Miao ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Nuclear Translocation ◽  
Colonic Cancer ◽  
Coiled Body ◽  
Histone H2a ◽  
Neoplastic Tissue ◽  
Colorectal Tumorigenesis ◽  
Underlying Mechanisms ◽  
Cancer Tissues

Atypical chemokine receptor 3 (ACKR3) has emerged as a key player in several biologic processes. However, much less is known the underlying mechanisms of ACKR3 in promoting tumorigenesis. We found, in human and animal model, that activation of ACKR3 promotes colorectal tumorigenesis through the NOLC1-induced perturbations of rRNA biogenesis. As compared with non-neoplastic tissue, human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with increased severity of colonic cancer. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing nuclear β-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of β-arrestin-1 (β-arr1), leading to the interaction of β-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion: ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear β-arr1-induced interaction of NOLC1 with Fibrillarin.

Atypical chemokine receptor 3 (ACKR3) induces the perturbation of rRNA biogenesis in colonic cells: a novel mechanism of colorectal tumorigenesis

2021 ◽  
Author(s):  
Juan Yang ◽  
Ya-Nan Li ◽  
Ting Pan ◽  
Rong-Rong Miao ◽  
Yue-Ying Zhang ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Ribosome Biogenesis ◽  
Nuclear Translocation ◽  
Colonic Cancer ◽  
Coiled Body ◽  
Histone H2a ◽  
Colorectal Tumorigenesis ◽  
Main Regulator

Abstract Background Atypical chemokine receptor 3 (ACKR3) has emerged as a key player in several biologic processes. Its atypical “intercepting receptor” signaling properties have established ACKR3 as the main regulator in many pathophysiological processes. In this study, we investigated the mechanisms of ACKR3 in promoting Colitis and colorectal tumorigenesis. Methods ACKR3 and clinically relevant was evaluated in human colonic cancer specimens. The mechanism of ACKR3-induced perturbation of rRNA biogenesis was performed in Villin-ACKR3-IREF mice specifically expressed ACKR3 in intestines. Nuclear β-arr1 and the interaction of NOLC1 to Fibrillarin were analyzed in vitro and in vivo assays. Results Activation of ACKR3 promotes Colitis and colorectal tumorigenesis, in human and animal model, through NOLC1-induced perturbations of rRNA biogenesis. Human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with the increased severity of Colitis and colorectal tumorigenesis. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing the nuclear β-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of β-arrestin-1 (β-arr1), leading to the interaction of β-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion ACKR3 promotes Colitis and colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear β-arr1-induced interaction of NOLC1 with Fibrillarin.

scholarly journals Starvation Induced Autophagy Promotes The Progression of Bladder Cancer By LDHA Mediated Metabolic Reprogramming

2021 ◽  
Author(s):  
Tinghao Li ◽  
Hang Tong ◽  
Hubin Yin ◽  
Yi Luo ◽  
Junlong Zhu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Malignant Progression ◽  
Metabolic Reprogramming ◽  
Transcriptional Expression ◽  
Regulatory Relationship ◽  
Underlying Mechanisms ◽  
Cancer Tissues ◽  
Interfering Rna

Abstract Background: Aberrantly autophagy and preternatural elevated glycolysis are prevalent in bladder cancer (BLCA), which are both related to malignant progression. But the regulatory relationship between autophagy and glycolytic metabolism remains unveiled. We imitated a starvation condition of tumor microenvironment and found significantly increased level of autophagy and aerobic glycolysis, which both regulated progression of BLCA cells. We further explored regulatory relationships and mechanisms between them.Methods: We used immunoblotting, immunofluorescence and transmission electron microscopy to detect autophagy levels of BLCA cells under different treatment. Lactate and glucose concentration detection demonstrated changes on glycolysis. Expression of lactate dehydrogenase A (LDHA) were detected at transcriptional and translational levels, which were also silenced by small interfering RNA and effects on malignant progression further tested. Underlying mechanisms on signaling pathways were performed by western blot, immunofluorescence and immunoprecipitation assays.Results: Starvation induced autophagy, regulated glycolysis by up-regulating expression of LDHA and caused progressive changes in BLCA cells. Mechanically, after starved ubiquitination modification of Axin1 increased and combined with P62, further degraded by autophagy-lysosome pathway. Liberated β-catenin nuclear translocation increased, binding with LEF1/TCF4 and promotes LDHA transcriptional expression. Also, high expression of LDHA was observed in cancer tissues and positively related to progression.Conclusion: Our study demonstrated that starvation-induced autophagy modulates glucose metabolic reprogramming by enhances Axin1 degradation and β-catenin nuclear translocation in BLCA, which promotes transcriptional expression of LDHA and further malignant progression.

scholarly journals N-Terminal Acetyltransferase Naa40p Whereabouts Put into N-Terminal Proteoform Perspective

2021 ◽  
Vol 22 (7) ◽  
pp. 3690
Author(s):  
Veronique Jonckheere ◽  
Petra Van Damme
Keyword(s):  
Amino Acid ◽  
Subcellular Localization ◽  
Nuclear Import ◽  
Ribosome Biogenesis ◽  
Regulatory Protein ◽  
Ectopic Expression ◽  
Cytoplasmic Localization ◽  
Histone H2a ◽  
Histone H4 ◽  
Nucleolar Proteins

The evolutionary conserved N-alpha acetyltransferase Naa40p is among the most selective N-terminal acetyltransferases (NATs) identified to date. Here we identified a conserved N-terminally truncated Naa40p proteoform named Naa40p25 or short Naa40p (Naa40S). Intriguingly, although upon ectopic expression in yeast, both Naa40p proteoforms were capable of restoring N-terminal acetylation of the characterized yeast histone H2A Naa40p substrate, the Naa40p histone H4 substrate remained N-terminally free in human haploid cells specifically deleted for canonical Naa40p27 or 237 amino acid long Naa40p (Naa40L), but expressing Naa40S. Interestingly, human Naa40L and Naa40S displayed differential expression and subcellular localization patterns by exhibiting a principal nuclear and cytoplasmic localization, respectively. Furthermore, Naa40L was shown to be N-terminally myristoylated and to interact with N-myristoyltransferase 1 (NMT1), implicating NMT1 in steering Naa40L nuclear import. Differential interactomics data obtained by biotin-dependent proximity labeling (BioID) further hints to context-dependent roles of Naa40p proteoforms. More specifically, with Naa40S representing the main co-translationally acting actor, the interactome of Naa40L was enriched for nucleolar proteins implicated in ribosome biogenesis and the assembly of ribonucleoprotein particles, overall indicating a proteoform-specific segregation of previously reported Naa40p activities. Finally, the yeast histone variant H2A.Z and the transcriptionally regulatory protein Lge1 were identified as novel Naa40p substrates, expanding the restricted substrate repertoire of Naa40p with two additional members and further confirming Lge1 as being the first redundant yNatA and yNatD substrate identified to date.

scholarly journals IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Miao Tian ◽  
Xiumei Wang ◽  
Jihong Sun ◽  
Wenlong Lin ◽  
Lumin Chen ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Nuclear Translocation ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Colorectal Tumorigenesis ◽  
Genetic Ablation ◽  
Prognosis Marker ◽  
Immune Sensing ◽  
Innate Immune Sensing

AbstractOccurrence of Colorectal cancer (CRC) is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis.

Eukaryotic Ribosome Assembly

2019 ◽  
Vol 88 (1) ◽  
pp. 281-306 ◽  
Author(s):  
Jochen Baßler ◽  
Ed Hurt
Keyword(s):  
Ribosomal Rna ◽  
Nuclear Export ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Cryo Electron Microscopy ◽  
A Cell ◽  
Cellular Pathways ◽  
Nucleolar Rnas ◽  
Shed Light

Ribosomes, which synthesize the proteins of a cell, comprise ribosomal RNA and ribosomal proteins, which coassemble hierarchically during a process termed ribosome biogenesis. Historically, biochemical and molecular biology approaches have revealed how preribosomal particles form and mature in consecutive steps, starting in the nucleolus and terminating after nuclear export into the cytoplasm. However, only recently, due to the revolution in cryo–electron microscopy, could pseudoatomic structures of different preribosomal particles be obtained. Together with in vitro maturation assays, these findings shed light on how nascent ribosomes progress stepwise along a dynamic biogenesis pathway. Preribosomes assemble gradually, chaperoned by a myriad of assembly factors and small nucleolar RNAs, before they reach maturity and enter translation. This information will lead to a better understanding of how ribosome synthesis is linked to other cellular pathways in humans and how it can cause diseases, including cancer, if disturbed.

scholarly journals Controlling the material properties and rRNA processing function of the nucleolus using light

2019 ◽  
Vol 116 (35) ◽  
pp. 17330-17335 ◽  
Author(s):  
Lian Zhu ◽  
Tiffany M. Richardson ◽  
Ludivine Wacheul ◽  
Ming-Tzo Wei ◽  
Marina Feric ◽  
...  
Keyword(s):  
Phase Behavior ◽  
Ribosomal Rna ◽  
Material Properties ◽  
Viscoelastic Properties ◽  
Ribosome Biogenesis ◽  
Threshold Concentration ◽  
Rrna Processing ◽  
Small Proteins ◽  
Nucleolar Material ◽  
Processing Steps

The nucleolus is a prominent nuclear condensate that plays a central role in ribosome biogenesis by facilitating the transcription and processing of nascent ribosomal RNA (rRNA). A number of studies have highlighted the active viscoelastic nature of the nucleolus, whose material properties and phase behavior are a consequence of underlying molecular interactions. However, the ways in which the material properties of the nucleolus impact its function in rRNA biogenesis are not understood. Here we utilize the Cry2olig optogenetic system to modulate the viscoelastic properties of the nucleolus. We show that above a threshold concentration of Cry2olig protein, the nucleolus can be gelled into a tightly linked, low mobility meshwork. Gelled nucleoli no longer coalesce and relax into spheres but nonetheless permit continued internal molecular mobility of small proteins. These changes in nucleolar material properties manifest in specific alterations in rRNA processing steps, including a buildup of larger rRNA precursors and a depletion of smaller rRNA precursors. We propose that the flux of processed rRNA may be actively tuned by the cell through modulating nucleolar material properties, which suggests the potential of materials-based approaches for therapeutic intervention in ribosomopathies.

scholarly journals High TRAF6 Expression Is Associated With Esophageal Carcinoma Recurrence and Prompts Cancer Cell Invasion

2017 ◽  
Vol 25 (4) ◽  
pp. 485-493 ◽  
Author(s):  
Xinyang Liu ◽  
Zhichao Wang ◽  
Guoliang Zhang ◽  
Qikun Zhu ◽  
Hui Zeng ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Tumor Necrosis Factor Receptor ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Underlying Mechanisms ◽  
Patient Prognosis ◽  
Cancer Tissues

Esophageal cancer is one of the most common types of cancer, and it has a poor prognosis. The molecular mechanisms of esophageal cancer progression remain largely unknown. In this study, we aimed to investigate the clinical significance and biological function of tumor necrosis factor receptor-associated factor 6 (TRAF6) in esophageal cancer. Expression of TRAF6 in esophageal cancer was examined, and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of functional and mechanism assays were performed to further investigate the function and underlying mechanisms in esophageal cancer. Expression of TRAF6 was highly elevated in esophageal cancer tissues, and patients with high TRAF6 expression have a significantly shorter survival time than those with low TRAF6 expression. Furthermore, loss-of-function experiments showed that knockdown of TRAF6 significantly reduced the migration and invasion abilities of esophageal cancer cells. Moreover, the pro-oncogenic effects of TRAF6 in esophageal cancer were mediated by the upregulation of AEP and MMP2. Altogether, our data suggest that high expression of TRAF6 is significant for esophageal cancer progression, and TRAF6 indicates poor prognosis in esophageal cancer patients, which might be a novel prognostic biomarker or potential therapeutic target in esophageal cancer.

scholarly journals Bystin in human cancer cells: intracellular localization and function in ribosome biogenesis

2007 ◽  
Vol 404 (3) ◽  
pp. 373-381 ◽  
Author(s):  
Masaya Miyoshi ◽  
Tetsuya Okajima ◽  
Tsukasa Matsuda ◽  
Michiko N. Fukuda ◽  
Daita Nadano
Keyword(s):  
Cell Proliferation ◽  
Cell Growth ◽  
Ribosomal Rna ◽  
Mammalian Cells ◽  
Ribosome Biogenesis ◽  
Human Cancer ◽  
Intracellular Localization ◽  
Promote Cell Proliferation ◽  
Human Cancer Cell Lines ◽  
Nucleolar Stress

Although bystin has been identified as a protein potentially involved in embryo implantation (a process unique to mammals) in humans, the bystin gene is evolutionarily conserved from yeast to humans. DNA microarray data indicates that bystin is overexpressed in human cancers, suggesting that it promotes cell growth. We undertook RT (reverse transcription)–PCR and immunoblotting, and confirmed that bystin mRNA and protein respectively are expressed in human cancer cell lines, including HeLa. Subcellular fractionation identified bystin protein as nuclear and cytoplasmic, and immunofluorescence showed that nuclear bystin localizes mainly in the nucleolus. Sucrose gradient ultracentrifugation of total cytoplasmic ribosomes revealed preferential association of bystin with the 40S subunit fractions. To analyse its function, bystin expression in cells was suppressed by RNAi (RNA interference). Pulse–chase analysis of ribosomal RNA processing suggested that bystin knockdown delays processing of 18S ribosomal RNA, a component of the 40S subunit. Furthermore, this knockdown significantly inhibited cell proliferation. Our findings suggest that bystin may promote cell proliferation by facilitating ribosome biogenesis, specifically in the production of the 40S subunit. Localization of bystin to the nucleolus, the site of ribosome biogenesis, was blocked by low concentrations of actinomycin D, a reagent that causes nucleolar stress. When bystin was transiently overexpressed in HeLa cells subjected to nucleolar stress, nuclear bystin was included in particles different from the nuclear stress granules induced by heat shock. In contrast, cytoplasmic bystin was barely affected by nucleolar stress. These results suggest that, while bystin may play multiple roles in mammalian cells, a conserved function is to facilitate ribosome biogenesis required for cell growth.

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