UBAP2L silencing inhibits cell proliferation and G2/M phase transition in breast cancer

He, Jing; Chen, Yuanping; Cai, Le; Li, Zelei; Guo, Xiaoqing

doi:10.1007/s12282-017-0820-x

Cited by 36 publications

(42 citation statements)

References 25 publications

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“…It can interact with BIM1 to form a complex that modulates hematopoietic stem cell activity [24]. Numerous studies indicated its association with various types of cancer [25][26][27][28][29][30]. It is required for the accurate distribution of chromosomes during mitosis [31].…”

Section: Introductionmentioning

confidence: 99%

UBAP2L arginine methylation by PRMT1 modulates stress granule assembly

et al. 2019

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Stress granules (SGs) are discrete assemblies of stalled messenger ribonucleoprotein complexes (mRNPs) that form when eukaryotic cells encounter environmental stress. RNA-binding proteins (RBPs) mediate their condensation by recruiting populations of mRNPs. However, the cellular and molecular mechanisms underlying the role of ubiquitin-associated protein 2-like (UBAP2L) in the regulation of SG dynamics remain elusive. Here, we show that UBAP2L is required for both SG assembly and disassembly. UBAP2L overexpression nucleated SGs under stress-null conditions. The UBAP2L Arg-Gly-Gly (RGG) motif was required for SG competence, and mediated the recruitment of SG components, including mRNPs, RBPs, and ribosomal subunits. The domain of unknown function (DUF) of UBAP2L-mediated interaction with ras GTPase-activating protein-binding protein (G3BP)1/2, and its deletion caused the cytoplasmic-nuclear transport of UBAP2L and G3BP1/2, thereby compromising SG formation. The protein arginine methyltransferase PRMT1 asymmetrically dimethylated UBAP2L by targeting the RGG motif. Increased arginine methylation blocked, whereas its decrease enhanced UBAP2L interactions with SG components, ablating and promoting SG assembly, respectively. These results provide new insights into the mechanisms by which UBAP2L regulates SG dynamics and RNA metabolism.

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Section: Introductionmentioning

confidence: 99%

UBAP2L arginine methylation by PRMT1 modulates stress granule assembly

et al. 2019

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“…Aside from neurodegeneration, a number of publications show a role of UBAP2L in cancer. UBAP2L appears to act in different malignances as an oncogene, whose expression is required for survival (Chai et al, 2016), growth (He et al, 2018; Li and Huang, 2014; Li et al, 2018; Zhao et al, 2015), and metastasization (Aucagne et al, 2017; Li and Huang, 2014; Li et al, 2018; Ye et al, 2017). Stress granules are often present in cancer cells (reviewed in Mahboubi and Stochaj, 2017), where they may promote cell survival in the stressful condition of the cancer microenvironment (Adjibade et al, 2015; Somasekharan et al, 2015; Vilas-Boas et al, 2016) and metastasization (Somasekharan et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…The relative stability of stress granule cores has recently allowed their purification and the identification of novel stress granule nucleators, among them the protein UBAP2L (Ubiquitin-associated protein 2-like (Markmiller et al, 2018; Youn et al, 2018). UBAP2L is a ubiquitous and abundant protein in human tissues (Beck et al, 2011; Lonsdale et al, 2013; Melé et al, 2015; Uhlén et al, 2015), it promotes cancer progression and metastasis (Aucagne et al, 2017; Chai et al, 2016; He et al, 2018; Li and Huang, 2014; Li et al, 2018; Ye et al, 2017, P. 20; Zhao et al, 2015) and may be involved in neurodegenerative diseases (Markmiller et al, 2018). Despite its abundance and potential implication in diseases, the exact role of UBAP2L in cell physiology and stress granule formation is not yet understood.…”

Section: Introductionmentioning

confidence: 99%

Molecularly distinct cores coexist inside stress granules

Cirillo

Cieren

Gotta

2019

Preprint

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L.C.), 15 monica.gotta@unige.ch (M.G.) 16 17 18 RESULTS 76UBAP2L localizes inside stress granules in discrete particles distinct from G3BP1 77 cores. 78 Given the importance of UBAP2L in sodium arsenite (arsenite hereafter)-induced stress 79 granule assembly (Markmiller et al., 2018; Youn et al., 2018), we sought to investigate its 80 sublocalization inside stress granules. To this end, we used 3D-STED (3D Stimulated 81 Emission Depletion miscroscopy, Hell and Wichmann, 1994; Klar and Hell, 1999). 3D-STED 82 immunofluorescence of HeLa K cells fixed and stained with anti-UBAP2L antibodies, 83 revealed that each stress granule is formed by discrete UBAP2L particles of roughly round 84 shape ( Fig. 1 A), with a diameter of 187.0 ± 44.2 nm (mean ± SD, Fig. 1 B). We also 85 performed 3D-STED on HeLa K cells stained for the known stress granule component 86 G3BP1 and measured the diameter of G3BP1 cores ( Fig. 1 A). Our analysis revealed a 87 diameter of 182.7 ± 41.9 nm (mean ± SD), which is in good agreement with the published 88 diameter of 190.8 ± 28.3 nm (Fig. 1B, Jain et al., 2016). The number of UBAP2L and G3BP1 89 particles linearly correlated with the stress granule volume ( Fig. S1 A). The localization of 90 UBAP2L in discrete particles and their size distribution suggest that UBAP2L localizes to 91 stress granule cores. 92The shell and the core of stress granules do not only differ in their composition, but also in 93 the dynamics of their components, with core proteins being more stable and shell proteins 94 more dynamic. To assess whether UBAP2L particles are stress granule cores, we measured 95 the dynamics of UBAP2L in living cells. To visualize UBAP2L, we tagged endogenous 96 UBAP2L at the C-terminus with the red fluorescent protein mScarlet using CRISPR-Cas9 97 (Fig. S1 B Bindels et al., 2017). Clones were screened via PCR (Polymerase Chain 98 Reaction, Fig. S1 C) and validated with western blot using an anti-UBAP2L antibody (Fig. 99 S1 D). In addition, treatment of UBAP2L-mScarlet HeLa cells with a siRNA directed against 100 mScarlet, followed by western blot analysis, confirmed the successful insertion of the 101 construct (Fig. S1 E). Although we failed to identify a homozygous insertion (Fig. S1 D, E), 102 live cell imaging revealed that UBAP2L-mScarlet transitions from a diffuse cytosolic signal 103 to a droplet-like pattern following arsenite exposure (Fig. S1 F). This observation is 104 consistent with published immunofluorescence of UBAP2L (Markmiller et al., 2018; Youn et 105 al., 2018), indicating that UBAP2L-mScarlet recapitulates the localization of wild-type 106 UBAP2L. Having created a tool to visualize UBAP2L in vivo, we next measured the 107 dynamics of UBAP2L in stress granules using Fluorescence Recovery after Photobleaching 108 (FRAP). After treating UBAP2L-mScarlet HeLa cells with arsenite to induce stress granule 109 6 formation, we bleached a single cytosolic granule and followed the fluorescence recovery 110 over time using confocal microscopy (Fig. 1 C). Analysis of fluo...

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“…After the functional enrichment analysis, we found that some enriched biological processes were reported to be associated with tumor progression. For example, i) cell adhesion was usually reported to show a reduced number of tumor cells since 1962 (Holmberg 1962); ii) autophagic cell death occurs via the activation of autophagy, which has been reported to play roles in tumor suppression (Mathew et al 2009); iii) the positive regulation of cell proliferation is a common characteristic of cancer, and the inhibition of cancer cell proliferation may serve as a potential target for cancer treatment (He et al 2018); iv) changes in extracellular matrix organization were reported with crucial roles in cancer metastasis (Goreczny et al 2017;Sada et al 2016); v) positive regulation of blood coagulation was frequently reported in cancer progression (Tikhomirova et al 2016); and vi) angiogenesis is still considered a common characteristic of tumorigenesis in many studies (Baltrunaite et al 2017;Protopsaltis et al 2019;Ziegler et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Peer Review #1 of "Urine proteome changes in rats subcutaneously inoculated with approximately ten tumor cells (v0.1)"

2019

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Background: Biomarkers are changes associated with the disease. Urine is not subject to homeostatic control and therefore accumulates very early changes, making it an ideal biomarker source. Usually, we have performed urinary biomarker studies involving at least thousands of tumor cells. However, no tumor starts from a thousand tumor cells. We therefore examined urine proteome changes in rats subcutaneously inoculated with approximately ten tumor cells. Methods: Here, we serially diluted Walker-256 carcinosarcoma cells to a concentration of 10 2 /mL and subcutaneously inoculated 0.1 mL of these cells into nine rats. The Urine proteomes on days 0, 13 and 21 were analyzed by liquid chromatography coupled with tandem mass spectrometry. Results: Hierarchical clustering analysis showed that the urine proteome of each sample at three time points were clustered into three clusters, indicating the good consistency of these nine rats when inoculated with the same limited tumor cells. Differential proteins on days 13 and 21 were mainly associated with cell adhesion, autophagic cell death, changes in extracellular matrix organization, angiogenesis, and the pentose phosphate pathway. All of these enriched functional processes were reported to contribute to tumor progression and could not be enriched through random allocation analysis. Conclusions: Our results indicated that 1) the urine proteome reflects changes associated with cancer even with only approximately ten tumor cells in the body and that 2) the urine proteome reflects pathophysiological changes in the body with extremely high sensitivity and provides potential for a very early screening process of clinical patients.

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UBAP2L silencing inhibits cell proliferation and G2/M phase transition in breast cancer

Cited by 36 publications

References 25 publications

UBAP2L arginine methylation by PRMT1 modulates stress granule assembly

UBAP2L arginine methylation by PRMT1 modulates stress granule assembly

Molecularly distinct cores coexist inside stress granules

Peer Review #1 of "Urine proteome changes in rats subcutaneously inoculated with approximately ten tumor cells (v0.1)"

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