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Effects of re-expressed RASSF1A on gene expression in rhabdoid tumor of the kidney cells.

ABSTRACT: Several groups reported the correlation between hypermethylation of RASSF1A and aggressiveness or a poor outcome in various pediatric tumors, including Wilms tumor. In addition, it is known that the overexpression of RASSF1A promotes apoptotic cell cycle arrest and reduces the tumorigenicity. In an attempt to identify epigenetic targets related to the biological features of rhabdoid tumor of the kidney (RTK), we analyzed the methylation level of the RASSF1A gene in RTK. RASSF1A promoter region in RTK is hypermethylated and the gene and protein expression levels were low. To examine the effect of re-expression of RASSF1A in RTK cells from the viewpoint of gene expression, we performed micro array analysis. We observed neither clear apoptosis induction nor cell-cycle arrest in RASSF1A-expressed RTK cell lines. Furthermore, the geneexpression profiling induced by RASSF1A expression in RTK cell line is curious, and CDK6 expression was significantly increased while CDKN2A expression was significantly decreased after RASSF1A expression. The changes in the gene expression profile that we observed in RTK cells after RASSF1A expression may not be causative events involving the suppression of cell proliferation, but rather antagonizingevents reflecting cellular responses against RASSF1A expression in RTK cells that are deficient in SMARCB1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171508 | GEO | 2024/04/05

REPOSITORIES: GEO

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Mus musculus

Project description:MicroRNA expression during cell cycle arrest

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The tumor suppressor Rassf1a prevents mouse liver tumorigenesis and regulates levels of the oncogenic kinase Tbk1 and of beta tubulin gene expression in the liver

Project description:The tumor suppressor gene RASSF1A (Ras association domain family protein 1A) coding for a microtubule stabilizing protein is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologues of the Drosophila Hippo kinase, RASSF1A is a potential regulator of the Hippo tumor suppressor pathway. RASSF1A shares these properties with the scaffold protein SAV1. The role of this pathway in human cancer has remained enigmatic because Hippo pathway components are rarely mutated. Rassf1a homozygous knockout mice developed liver tumors. However, heterozygous deletion of Sav1 or co-deletion of Rassf1a and Sav1 produced liver tumors with much higher efficiency than single deletion of Rassf1a. Analysis of RASSF1A binding partners by mass spectrometry identified the Hippo kinases MST1, MST2 and the oncogenic IkB kinase TBK1 as the most significantly enriched RASSF1A-interacting proteins. The transcriptome of Rassf1a-/- livers was more deregulated than that of Sav1+/- livers and the transcriptome of Rassf1a-/-, Sav1+/- livers was similar to that of Rassf1a-/- mice. We found that the levels of Tbk1 protein were substantially upregulated in livers lacking Rassf1a, and at the transcript level, factors regulating Tbk1 stability, including Usp2 and Dtx4, were also dysregulated. Furthermore, transcripts of several beta tubulin isoforms were increased in the Rassf1a-deficient liver genotypes presumably reflecting a role of Rassf1a as a tubulin-binding and microtubule-stabilizing protein. Our data suggest a multifactorial role of Rassf1a in suppression of liver carcinogenesis.

2016-05-31 | GSE73911 | GEO

MUC1-C represses the RASSF1A tumor suppressor and activated Kras signaling in human carcinoma cells

Project description:RASSF1A encodes a tumor suppressor that inhibits RAS’RAF’MEK’ERK signaling and is one of the most frequently inactivated genes in human cancers. MUC1-C is an oncogenic effector of the cancer cell epigenome that is overexpressed in diverse carcinomas. We show here that MUC1-C represses RASSF1A expression in multiple types of KRAS wild-type and mutant cancer cells. Mechanistically, MUC1-C occupies the RASSF1A promoter in a complex with the ZEB1 transcriptional repressor. In turn, MUC1-C/ZEB1 complexes recruit DNA methyltransferase 3b (DNMT3b) to the CpG island in the RASSF1A promoter. Targeting MUC1-C, ZEB1 and DNMT3b thus decreases methylation of the CpG island and derepresses RASSF1A transcription. We also show that targeting MUC1-C downregulates KRAS signaling with decreases in MEK/ERK activation, which is of importance for RAS-mediated tumorigenicity. These findings define a previously unrecognized role for MUC1-C in suppression of RASSF1A and support targeting MUC1-C as an approach for inhibiting KRAS signaling.

2019-05-27 | GSE123860 | GEO

The tumor suppressor Rassf1a prevents mouse liver tumorigenesis and regulates levels of the oncogenic kinase Tbk1 and of beta tubulin gene expression in the liver

2016-05-31 | E-GEOD-73911 | biostudies-arrayexpress

RASSF1A IS REQUIRED FOR THE MAINTENANCE OF NUCLEAR ACTIN LEVELS

Project description:Nuclear actin participates in many essential cellular processes including gene transcription, chromatic remodelling and mRNA processing. Actin shuttles into and out the nucleus through the action of dedicated transport receptors importin-9 and exportin-6, but how this transport is regulated remains unclear. Here we show that RASSF1A is a novel regulator of actin nucleocytoplasmic trafficking and is required for the active maintenance of nuclear actin levels through supporting binding of exportin-6 (XPO6) to RAN GTPase. RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor gene frequently silenced by promoter hypermethylation in all major solid cancers. Specifically, we demonstrate that endogenous RASSF1A localizes to the nuclear envelope (NE) and is required for nucleo-cytoplasmic actin transport and the concomitant regulation of Myocardin-related transcription factor A (MRTF-A), a coactivator of the transcription factor serum response factor (SRF). The RASSF1A/RAN/XPO6/nuclear actin pathway is aberrant in cancer cells where RASSF1A expression is lost and correlates with reduced MTRF/SRF activity leading to cell adhesion defects. Taken together, we have identified a previously unknown mechanism by which the nuclear actin pool is regulated and uncovered a previously unknown link of RASSF1A and MTRF/SRF in tumor suppression.

2019-05-30 | PXD011517 | Pride

Modulator of Apoptosis 1 (MOAP-1) is a highly regulated tumor suppressor protein

Project description:Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in both the intrinsic and extrinsic modes of cell death or apoptosis. It is an integral partner to the tumor suppressor Ras association domain family 1A (RASSF1A) and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor is yet to be determined. In this study, we present several lines of evidence from cancer databases, immnoblotting of cancer cells, proliferation and xenograft assays to demonstrate the role of MOAP-1 as a tumor suppressor. MOAP-1 overexpressed tumors display upregulation of multiple genes including several pro-apoptotic members that may influence the role of MOAP-1 in cell death. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to enhanced proteasomal degradation. The loss of RASSF1A is an early marker of tumorigenesis and we speculate that the additional loss of function of MOAP-1 may be a second “hit” to functionally compromise the RASSF1A/MOAP-1 death receptor dependent pathway and drive tumorigensis.

2015-11-02 | GSE43990 | GEO

RASSF1A controls Tissue Stiffness and Cancer Stem-like Cells in Lung Adenocarcinoma

Project description:Lung cancer remains the leading cause of cancer-related death due to poor treatment responses and resistance arising from tumor heterogeneity. Here we show that adverse prognosis associated with epigenetic silencing of the tumour suppressor RASSF1A is due to increased deposition of extracellular matrix (ECM), tumour stiffness and metastatic dissemination in vitro and in vivo. We find that lung cancer cells with RASSF1A promoter methylation display constitutive nuclear YAP1 and expression of collagen prolylhydroxylase (P4HA2) which increases collagen deposition. Furthermore, we identify that elevated collagen creates a stiff-ECM which in turn triggers cancer stem-like programming and metastatic dissemination in vivo. Re-expression of RASSF1A or inhibition of P4HA2 activity reverse these effects and increase markers of lung differentiation (TTF-1, Mucin5B). Our study identifies RASSF1A as a clinical biomarker associated with mechanical properties of ECM which increases levels of cancer stemness and risk of metastatic progression in lung adenocarcinoma. Moreover, we highlight P4HA2 as a potential target for uncoupling ECM signals that support cancer stemness.

2019-05-20 | PXD012694 | Pride

Ras-Association Domain Family 1C Protein Promotes Breast Cancer Cell Migration

Project description:RASSF1C, unlike RASSF1A, is not a tumor suppressor, but instead may play a role in stimulating metastasis and survival in breast cancer cells RASSF1C over-expression enhances T47D cell invasion/migration in vitro

2010-10-02 | GSE24473 | GEO

Iwamoto2010 - Cell cycle reponse to DNA damage

Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.

2020-04-27 | BIOMD0000000939 | BioModels

Modulator of Apoptosis 1 (MOAP-1) is a highly regulated tumor suppressor protein

Project description:Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in both the intrinsic and extrinsic modes of cell death or apoptosis. It is an integral partner to the tumor suppressor Ras association domain family 1A (RASSF1A) and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor is yet to be determined. In this study, we present several lines of evidence from cancer databases, immnoblotting of cancer cells, proliferation and xenograft assays to demonstrate the role of MOAP-1 as a tumor suppressor. MOAP-1 overexpressed tumors display upregulation of multiple genes including several pro-apoptotic members that may influence the role of MOAP-1 in cell death. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to enhanced proteasomal degradation. The loss of RASSF1A is an early marker of tumorigenesis and we speculate that the additional loss of function of MOAP-1 may be a second âhitâ to functionally compromise the RASSF1A/MOAP-1 death receptor dependent pathway and drive tumorigensis. RNA was isolated mouse xenographs generated with the HCT116 cell line transfected with wild type Myc-tagged MOAP-1, empty Vector or the Myc-tagged MOAP-1 mutants K278R or K264R in triplicate. Pairwise gene expression differences were compared the two samples. Features selected had more than 1.5-fold up-or down-regulated (P values of >05, unpaired Studentâs t-test).

2015-11-02 | E-GEOD-43990 | biostudies-arrayexpress

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