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Rac1-mediated DNA damage and inflammation promote Nf2 tumorigenesis but also limit cell cycle progression by inducing p53 checkpoint and cellular senescence

ABSTRACT: Neurofibromatosis type 2 (NF2) is caused by mutations of the tumor suppressor MERLIN/NF2. Prior studies established Yap as the driver of proliferation and tumorigenesis upon Nf2 inactivation in a well defined, genetically engineered murine liver model. Here, we report that in this model system Nf2 tumorigenesis also involves DNA damage and inflammation via Rac1-mediated production of ROS. Ablation of Rac1 blocks Nf2 tumorigenesis in spite of hyperactivation of the cyclinD1-pRb-E2F1 pathway and profound increase in liver size associated with the loss of Rac1-dependent p53 checkpoint and senescence programs. Surprisingly, Erk, Akt and Stat3 signaling does not correlate with proliferation or tumorigenesis despite being activated in Nf2 deficient livers, indicating a lesser role of these pathways for Nf2 tumorigenesis. Because a senescence gene signature is associated with benign NF2 tumors but not with malignant NF2 mutant mesotheliomas, we conclude that senescence may underlie the benign nature of NF2.

ORGANISM(S): Mus musculus

PROVIDER: GSE70742 | GEO | 2016/12/01

SECONDARY ACCESSION(S): PRJNA289469

REPOSITORIES: GEO

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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

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

Analysis of the transcriptomic profile of WT mouse embryonic fibroblast (MEF WT) and Nf2-knockout mouse embryonic fibroblast (MEF Nf2 KO) cell lines

Project description:Merlin is the tumor suppressor protein encoded by the NF2 gene. The expression of Merlin is remarkably decreased in metastatic breast cancer tissues irrespective of the breast cancer subtype. In order to ascribe clinical relevance, we re-capitulated the loss of Merlin in breast cancer cells. Merlin deficiency elicited a markedly invasive phenotype. In order to overcome the challenge of embryonic lethality of a total Nf2-knockout, we generated a unique mammary-specific Nf2-knockout mouse mammary tumor model. Both, the Nf2-knockout mouse embryonic fibroblasts (MEF) and Merlin-deficient breast tumor cells displayed a robust invasive phenotype. Transcriptomic assessment of Nf2-knockout MEFs revealed notable alterations in glutathione transferase and antioxidant networks indicating a role for Merlin in redox biology. This programmatic alteration resonated with the pathways that emerged from breast tumor cells engineered for Merlin deficiency.

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Proteomic analysis of the NF2/Merlin Interactome by Proximity Biotinylation

Project description:Neurofibromatosis type 2 is an inherited neoplastic disease consisting of schwannomas, meningiomas, and ependymomas that is caused by inactivation of the tumor suppressor gene NF2. The NF2 gene product, merlin, has no intrinsic catalytic activity; its tumor suppressor function is mediated through the proteins with which it interacts. However, there is no consensus about which merlin interactions are necessary for tumor suppression. We used proximity biotinylation followed by mass spectrometry and direct binding assays to characterize the proteins that associate with merlin and merlin mutants in immortalized Schwann cells. We identified 52 proteins that associate with merlin, including a previously unreported merlin binding protein, ASPP2. Our results identify merlin as a component of mechanosensing signal transduction pathways in cell junctions, in the context of a specific set of structures and molecules through which it acts, in a cell type relevant to schwannoma formation.

2019-04-25 | PXD012017 | Pride

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

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2022-03-24 | GSE186189 | GEO

Transcriptome changes of endothelial cells in mouse tumor by Nf2/Merlin

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2021-10-21 | GSE186162 | 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

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2013-06-19 | E-GEOD-48078 | biostudies-arrayexpress

Inactivation of p21-Activated Kinase 2 (Pak2) Inhibits the Development of Nf2-Deficient Tumors by Restricting Downstream Hedgehog and Wnt Signaling

Project description:Since loss of the NF2 tumor suppressor gene results in p21-activated kinase (Pak) activation, PAK inhibitors hold promise for the treatment of NF2-deficient tumors. To test this possibility, we asked if loss of Pak2, a highly expressed group I PAK member, affects the development of malignant mesothelioma in Nf2;Cdkn2a-deficient (NC) mice and the growth properties of NC mesothelioma cells in culture. In vivo, deletion of Pak2 resulted in a markedly decreased incidence and delayed onset of both pleural and peritoneal malignant mesotheliomas in NC mice. In vitro, Pak2 deletion decreased malignant mesothelioma cell viability, migration, clonogenicity, and spheroid formation. RNA-seq analysis demonstrated downregulated expression of Hedgehog and Wnt pathway genes in NC;Pak2-/- mesothelioma cells versus NC;Pak2+/+ mesothelioma cells. Targeting of the Hedgehog signaling component Gli1 or its target gene Myc inhibited cell viability and spheroid formation in NC;P+/+ mesothelioma cells. Kinome profiling uncovered kinase changes indicative of EMT in NC;Pak2-/- mesothelioma cells, suggesting that Pak2-deficient malignant mesotheliomas can adapt by reprogramming their kinome in the absence of Pak activity. The identification of such compensatory pathways offers opportunities for rational combination therapies to circumvent resistance to anti-PAK drugs.

2023-03-10 | PXD030571 | Pride

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