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Effect of FBL depletion on cell morphology

ABSTRACT: This study reveals a previously unrecognized role of FBL in maintaining epithelial characteristics. Its depletion led to a marked reduction in Scribble, a key basolateral protein required for stabilizing E-cadherin at the membrane and sustaining Hippo signaling, thereby preventing TAZ activation. Scribble’s bivalent promoter is pre-associated with H3K4me3, H3K27me3, and EZH2. As a nucleolar protein, FBL retains a fraction of EZH2 within the nucleolus, and its loss results in the redistribution of EZH2 into the nucleoplasm, where it engages PRC2-bound promoters, including that of Scribble.Diminished Scribble levels upon FBL knockdown disrupted Hippo signaling, leading to TAZ accumulation and subsequent upregulation of EMT drivers Snail and Foxc2. Additionally, Scribble modulates Akt activity via PHLPP1, and its depletion enhanced Akt-dependent phosphorylation of EZH2, compromising its methyltransferase function. In MCF10A (p53 DN) cells, loss of FBL increased mesenchymal markers (Snail, Twist, Zeb1) while down

ORGANISM(S): Homo sapiens

PROVIDER: GSE289801 | GEO | 2025/10/31

REPOSITORIES: GEO

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Yap1-Scribble polarization is required for hematopoietic stem cell division and fate

Project description:Yap1 and its paralogue Taz largely control epithelial tissue growth. We have identified that hematopoietic stem cell (HSC) fitness response to stress depends on Yap1 and Taz. Deletion of Yap1 and Taz induces a loss of HSC quiescence, symmetric self-renewal ability and renders HSC more vulnerable to serial myeloablative 5-fluorouracil treatment. This effect depends on the predominant cytosolic polarization of Yap1 through its PDZ domain-mediated interaction with the scaffold Scribble. Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity and HSC fate determination in vivo. Deletion of Scribble disrupts Yap1 co-polarization with Cdc42 and decreases Cdc42 activity, resulting in increased selfrenewing HSC with competitive reconstitution advantages. These data suggest that Scribble/Yap1 co-polarization is indispensable for Cdc42- dependent activity on HSC asymmetric division and fate. The combined loss of Scribble, Yap1 and Taz results in transcriptional upregulation of Rac-specific guanine nucleotide exchange factors, Rac activation and HSC fitness restoration. Scribble links Cdc42 and the cytosolic functions of the Hippo signaling cascade in HSC fate determination.

2020-05-30 | GSE151465 | GEO

CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling

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Transcription profile of FBL-knock down ES cells

Project description:Pluripotent stem cells have been shown to have unique nuclear properties, e.g., hyperdynamic chromatin and large, condensed nucleoli. However, the contribution of the latter unique nucleolar character to pluripotency has not been well understood. Here, we show fibrillarin (FBL), a critical methyltransferase for ribosomal RNA (rRNA) processing in nucleoli, as one of the proteins highly expressed in pluripotent embryonic stem (ES) cells. Stable expression of FBL in ES cells prolonged the pluripotent state of mouse ES cells cultured in the absence of leukemia inhibitory factor (LIF). Analyses using deletion mutants and a point mutant revealed that the methyltransferase activity of FBL regulates stem cell pluripotency. Knock down of this gene led to significant delays in rRNA processing, growth inhibition, and apoptosis in mouse ES cells. Interestingly, both partial knock down of FBL and treatment with actinomycin D, an inhibitor for rRNA synthesis, induced the expression of differentiation markers in the presence of LIF and promoted stem cell differentiation into neuronal lineages. Moreover, we identified p53 signaling as the regulatory pathway for pluripotency and differentiation of ES cells. These results suggest that proper activity of rRNA production in nucleoli is a novel factor for the regulation of pluripotency and differentiation ability of ES cells. Tc-inducible FBL-knock down ES cells were cultured for 2 days with or without Tc in the presence of LIF. These 2 conditions were analysed transcription profile.

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CLASH for 15.5K and FBL proteins in HEK293T cells

Project description:We performed CLASH for 15.5K and FBL in HEK293T cells which overexpressed 15.5K and FBL, respectively.

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LncRNAs regulate FBL to facilitate rRNA processing in cancer cells

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FBL catalyzes internal 2′-O-Methylation in mRNA to promote RNA stability

Project description:2′-O-Methylation is prominent in ribosome RNA catalyzed by Fibrillarin (FBL). However, the stoichiometry of 2′-O-methylation at base resolution in the internal mRNA and its functions remain to be explored. Here, we firstly investigate the effect of the 2′-O-methylation on the mRNA stability and expression at a genome-wide scale. Combined with Nanopore sequencing and a machine learning strategy, we identified thousands of RNA methylation sites in mRNA and rRNA at base resolution. The mRNA half-life profiling of FBL deficient cells established a direct effect of RNA methylation and FBL binding on the mRNA stability. We further determined the RNA methylation on the expression levels and tested the post-transcriptional effect of elevated FBL mediated 2′-O-Methylation in mRNA within the prostate cancer model. Besides the role of the translational regulation of FBL in rRNA, elevated FBL promotes cancer progress by stabilizing the mRNA through RNA binding and 2′-O-Methylation. Our results reveal a novel mechanism that FBL regulates the 2′-O-methylation and turnover of mRNA at whole transcriptome levels.

2024-06-20 | GSE208837 | GEO

Identification of PHLPP1 as a tumor suppressor reveals the role of feedback compensation in PTEN-mutant prostate cancer progression

Project description:Hyper-activation of the PI 3-Kinase/ AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, upon partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the co-deletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN-mutant prostate cancer to life-threatening disease. To better assess the role of Phlpp in prostate we performed micorarray analysis of gene expression in the WT and Pten+/-; Phlpp1-/- mice.

2011-08-16 | E-GEOD-30987 | biostudies-arrayexpress

Transcription profile of FBL-knock down ES cells

2014-08-01 | GSE51139 | GEO

A PRC2-independent function for EZH2 in regulating rRNA 2′-O methylation and IRES-dependent translation

Project description:Overactivated ribosome biogenesis is a common feature of cancer. However, the underlying molecular mechanism remains elusive. Herein, we report enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, could interact with fibrillarin (FBL) directly in the nucleolus. While loss of EZH2 does not impact FBL-mediated histone H2AQ104 methylation (H2AQ104me) and 18S rRNA processing, EZH2 is proved to be involved in rRNA 2′-O methylation in a manner dependent of its interaction with FBL. Mechanistically, EZH2 strengthens the fibrillarin (FBL)-NOP56 interaction by binding to both proteins and thus facilitates the assembly of box C/D small nucleolar ribonucleoprotein (box C/D snoRNP). Strikingly, EZH2 deficiency alters translational efficiency and reduces internal ribosome entry site (IRES) activity of key oncogenes in prostate cancer. In summary, our findings reveal a novel non-methyltransferase role of EZH2 that mediates FBL functions, which may provide more options for the development of EZH2-targeting curative strategies in cancer.

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