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Regulation of Primary Cilia Disassembly Through HUWE1-Mediated TTBK2 Degradation Plays a Crucial Role in Cerebellar Development and Medulloblastoma Growth

ABSTRACT: Regulation of Primary Cilia Disassembly Through HUWE1-Mediated TTBK2 Degradation Plays a Crucial Role in Cerebellar Development and Medulloblastoma Growth

PROVIDER: PRJNA1117916 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29224972_1.fastq.gz	Fastqsanger.gz
	SRR29224972_2.fastq.gz	Fastqsanger.gz
	SRR29224973_1.fastq.gz	Fastqsanger.gz
	SRR29224973_2.fastq.gz	Fastqsanger.gz
	SRR29224974_1.fastq.gz	Fastqsanger.gz

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Regulation of Primary Cilia Disassembly Through HUWE1-Mediated TTBK2 Degradation Plays a Crucial Role in Cerebellar Development and Medulloblastoma Growth

Project description:Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. Disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.

2024-06-03 | GSE268621 | GEO

Kinase pathways in cilia disassembly signalling

Project description:Aim: To determine the major protein kinase pathways altered upon serum- or LPA-induced cilia disassembly Primary cilia are dynamic structures which must disassemble for a cell to go through mitosis and re-assemble in G0 to transduce essential signals. Also, in non-cycling cells (such as renal epithelial cells), there is evidence to suggest that deregulated cilia disassembly is of critical importance, for example in instances with an excess of a cilia disassembly stimuli (such as Aurora kinase A expression and activation, a key disassembly factor) which is associated with ciliopathy phenotypes and a net loss of ciliated cells. Serum, growth factor or lysophosphatidic acid (LPA) stimulation of ciliated cells are well established experimental paradigms for the induction of cilia disassembly. The signalling network activated by these stimuli that culminates in cilia disassembly is complex and poorly understood. Studies have generally focused on a single or small group of proteins of interest to define their roles in cilia disassembly and the key pathways and kinases activated upon serum stimulation to induce cilia disassembly have not been defined. Moreover, to the best of our knowledge an unbiased analysis of the major pathways activated during cilia disassembly has not been performed. Ciliated hTERT-RPE1 cells were treated with 10% serum or 2 M LPA for 15’ or 2 h to initiate cilia disassembly + pan-class I PI3K inhibitor GDC-0941, followed by label-free phosphoproteomics.

2024-07-25 | PXD046462 | Pride

Regulation of primary cilia disassembly through HUWE1-mediated TTBK2 degradation plays a crucial role in cerebellar development and medulloblastoma growth.

Project description: Not available

| S-EPMC11445238 | biostudies-literature

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

Project description:We identified the ubiquitin ligase Huwe1 as a crucial regulator of hematopoietic stem cell (HSC) functions. We generated Huwe1 conditional knock-out mice and discovered that the loss of this ligase causes an increased proliferation and stem cell exhaustion, together with a decreased lymphoid specification in vivo. We observed that the ubiquitin ligase Huwe1 is controlling the expression of N-myc at the level of the most immature stem and progenitor hematopoietic populations, mediating the described effects. Hematopoietic stem cells (HSC) from the bone marrow of transgenic animals carrying a N-myc/mCherry fusion gene were sorted according to N-myc expression (defined by mCherry) into N-myc high and low subpopulations. Each of these 2 populations was subjected to microarray gene expression profiling.

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The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

2016-08-20 | GSE85832 | GEO

The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [high-throughput sequencing]

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Depletion of the E3 ubiquitin ligase HUWE1 impairs Kras-induced lung adenocarcinoma tumorigenesis and induces a senescent phenotype

Project description:The E3 ubiquitin ligase HUWE1 modifies a diverse network of substrate proteins by ubiquitination, through which it regulates various intracellular processes and contributes to both oncogenic and tumour suppressor mechanisms in different cancer contexts. Here, by analysing human lung adenocarcinoma (LUAD) patient samples we reveal that HUWE1 protein expression is commonly upregulated in LUAD tumours compared to normal adjacent lung tissue and that this increase is associated with tumour stage. Using multiple, independent murine models of LUAD initiation and growth, we identify that Huwe1 is essential for mutant Kras-induced lung tumour development and reveal a novel, p53-independent requirement for Huwe1 in LUAD. Mechanistically, we demonstrate induction of a senescent phenotype following HUWE1 depletion - characterised by impaired proliferation, an atypical cell cycle distribution, emergence of morphologically abnormal enlarged cells, and transcriptional reprogramming associated with inflammatory SASP signalling and NFkB activation. Together, these data highlight a crucial role for HUWE1 in mutant Kras-induced LUAD tumorigenesis and in the continued growth and proliferation of established LUAD cells, confirming HUWE1 as a rational therapeutic target for LUAD.

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Smoking is Associated with Shortened Airway Cilia

Project description:Background: Whereas cilia damage and reduced cilia beat frequency have been implicated as causative of reduced mucociliary clearance in smokers, theoretically mucociliary clearance could also be affected by cilia length. Based on models of mucociliary clearance predicting cilia length must exceed the 6 -7 μm airway surface fluid depth to generate force in the mucus layer, we hypothesized cilia height may be decreased in airway epithelium of normal smokers compared to nonsmokers. Methodology/Principal Findings: Cilia length in normal nonsmokers and smokers was evaluated in aldehyde-fixed, paraffin-embedded endobronchial biopsies, and air-dried and hydrated samples brushed from human airway epithelium via fiberoptic bronchoscopy. In 28 endobronchial biopsies, healthy smoker cilia length was reduced 15% compared to nonsmokers (p<0.05). In 47 air-dried samples of airway epithelial cells, smoker cilia length was reduced 13% compared to nonsmokers (p<0.0001). Analysis of the length of individual, detached cilia in 17 samples, smoker cilia length was reduced 9% compared to nonsmokers (p<0.05). Finally, in 16 fully hydrated, unfixed samples, smoker cilia length was reduced 7% compared to nonsmokers (p<0.05). Conclusions/significance: Models predict that a reduction in cilia length would reduce mucociliary clearance, suggesting that smoking-associated shorter airway epithelial cilia plays a significant role in the pathogenesis of smoking-induced lung disease.

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Epigenetic regulation of cilia stability and kidney development by the chromatin remodeling SWI/SNF complexes [72hpf]

Project description:Cilia are important subcellular organelles and are regulated by transcription factors including Foxj1 and Rfx proteins. Whether and how are cilia regulated at epigenetic level remains unknown. We addressed this question by knocking down or knocking out of chromatin remodeling genes. Interestingly, depletion of multiple components of the switch/sucrose non-fermentable (SWI/SNF) complexes lead to ciliopathy-like phenotypes in zebrafish embryos. Specifically, depletion of Actl6a, one of the components of the SWI/SNF complexes lead cilia disassembly and cystic kidney, but do not affect cilia motility. Omics studies show that in Actl6a-depleted embryos, a set of cilia genes including Foxj1a and Rfx2, the master regulators of cilia assembly, were downregulated at transcriptional level, chromatin accessibility and the SWI/SNF complexes binding. Thus, our study reveals that the SWI/SNF complexes regulate cilia stability and kidney development by direct modulating the expression Foxj1a and Rfx2.

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Epigenetic regulation of cilia stability and kidney development by the chromatin remodeling SWI/SNF complexes [30hpf]

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