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Growth inhibition by Merlin expression correlates with a cross-tissue transcriptional signature

ABSTRACT: We have found a broad case of tumour suppressor hypersensitivity for Merlin in cancer: Merlin expression in Merlin deficient cells (but not Merlin wild type cells) strongly suppresses proliferation regardless of tumour type or of additional somatic mutations. To study how Merlin selectively induced growth arrest in Merlin-deficient cells, global gene expression regulation by Merlin was examined by microarray in a set of four cell line pairs derived from different tumour types Four Merlin-deficient and four Merlin wild type cell lines derived from four different tissues/tumour types (meninges, thyroid, kidney, breast) were infected with pLEX lentiviruses (Open Biosystems) expressing either wt Merlin or Merlin L46R (a tumour-derived loss-of-function mutant, used as a control). 24 hours after infection, fresh media containing 2.5ug/ml puromycin was added (drug selection) and cells grown for a further 24 hours, i.e. cells were harvested 48hour after infection. RNA was analyzed using GeneChip Human Gene 2.0 ST arrays (Affymetrix). n=2 for Merlin-deficient cell lines; n=1 for Merlin wt cell lines

ORGANISM(S): Homo sapiens

SUBMITTER: Stephen Henderson

PROVIDER: E-GEOD-53494 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Growth inhibition by Merlin expression correlates with a cross-tissue transcriptional signature

Project description:We have found a broad case of tumour suppressor hypersensitivity for Merlin in cancer: Merlin expression in Merlin deficient cells (but not Merlin wild type cells) strongly suppresses proliferation regardless of tumour type or of additional somatic mutations. To study how Merlin selectively induced growth arrest in Merlin-deficient cells, global gene expression regulation by Merlin was examined by microarray in a set of four cell line pairs derived from different tumour types

2015-04-01 | GSE53494 | GEO

Transcriptional control by Merlin of contact inhibition and tissue homeostasis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-04-01 | E-GEOD-53501 | biostudies-arrayexpress

Merlin S13 phosphorylation controls meningioma Wnt signaling and magnetic resonance imaging features

Project description:Meningiomas are the most common primary intracranial tumors and are associated with inactivation of the tumor suppressor NF2/Merlin, but one-third of meningiomas retain Merlin expression and typically have favorable clinical outcomes. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that predict meningioma outcomes and could be used to guide treatment de-escalation or imaging surveillance of Merlin-intact meningiomas are lacking. Here we integrate single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma cells, xenografts, and human patients to define biochemical mechanisms and an imaging biomarker that distinguish Merlin-intact meningiomas with favorable clinical outcomes from meningiomas with unfavorable clinical outcomes. We find Merlin drives meningioma Wnt signaling and tumor growth through a feed-forward mechanism that requires Merlin dephosphorylation on serine 13 (S13) to attenuate inhibitory interactions with β-catenin and activate the Wnt pathway. Meningioma MRI analyses of xenografts and human patients show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC) on diffusionweighted imaging. In sum, our results shed light on Merlin posttranslational modifications that regulate meningioma Wnt signaling and tumor growth in tumors without NF2/Merlin inactivation. To translate these findings to clinical practice, we establish a non-invasive imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with favorable meningiomas.

2024-07-04 | PXD053578 | Pride

Merlin rescue drives Wnt signalling

Project description:To investigate the effect of Merlin rescue on cell proliferation in 3D, we grew subcutaneous xenografts from NF2-deficient CH-157MN meningioma cells harboring doxycycline inducible WT-Merlin. Mice were treated with or without doxycycline and Merlin induction was confirmed 24 hours after induction with Western blot. We performed single-cell RNA sequencing on five Merlin-deficient tumors and seven Merlin rescue tumors

2023-08-07 | GSE224347 | GEO

Gene expression signature regulated by cell density and Merlin/NF2 knockdown in HMLE cells

Project description:Merlin has been implicated in contact-dependent inhibition of proliferation To define genes regulated by Merlin and study their relationship to cell density-dependent gene expression, microarray experiments were performed after Merlin depletion in HMLE cells at both high and low cell densities. HMLE are non-transformed immortalized human mammary epithelial cells (Elenbaas et al., Genes Dev 15, 2001) HMLE cells were transfected with NF2 or scramble (control) siRNAs. 2 days later medium was changed (dense) or cells seeded in sparse conditions and RNA isolated the day after (3 days after siRNA transfection)

2015-04-01 | E-GEOD-53493 | biostudies-arrayexpress

Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus

Project description:Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4DCAF1, and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 induce a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlinâs ability to interact with or inhibit CRL4DCAF1. Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1. To examine if Merlin controls gene expression through inhibition of CRL4DCAF1, and define the general function of this ligase, we compared the gene expression program activated by expression of Merlin or by depletion of DCAF1 in Merlin-null FC-1801 mouse Schwannoma cells

2010-03-09 | E-GEOD-19305 | biostudies-arrayexpress

Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus

Project description:Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4DCAF1, and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 induce a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlin’s ability to interact with or inhibit CRL4DCAF1. Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1.

2010-02-25 | GSE19305 | GEO

Merlin/NF2-loss Driven Tumorigenesis Linked to CRL4(DCAF1)-Mediated Inhibition of the Hippo Pathway Components Lats1 and 2

Project description:Studies in drosophila have suggested that Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at or near the plasma membrane. In contrast, studies of Merlin-deficient tumor cells have indicated that Merlin suppresses tumorigenesis by entering into the nucleus where it inhibits the E3 ubiquitin ligase CRL4DCAF1. We found that CRL4DCAF1 promotes YAP and TEAD-dependent transcription by ubiquitylating and thereby inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2 mutant mesotheliomas, schwannomas and meningiomas. We conclude that de-repressed CRL4DCAF1 controls the output of the Hippo pathway by inhibiting Lats1 and 2 in the nucleus.

2014-07-15 | GSE56157 | GEO

Identification of Merlin ubiquitination sites

Project description:To identify the ubiquitination sites on Merlin, Flag-tagged wild-type Merlin or the S518D mutant were stably transduced into LN229 cells. These cells were treated with thapsigargin for 15 minutes and subjected to immunoprecipitation and followed by Mass Spectrometry.

2020-12-07 | PXD021057 | Pride

Identification of Merlin binding proteins

Project description:To identify proteins interacting with Merlin in response to calcium signaling, Flag-tagged Merlin was stably transduced into LN229 cells. These cells and empty vector-transduced LN229 cells were treated with DMSO or thapsigargin for 15 minutes and subjected to immunoprecipitation followed by Mass Spectrometry.

2020-12-07 | PXD021058 | Pride

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