Browse
Submit Data
Databases
API
Help

Dataset Information

41 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CD43 promotes cells transformation by preventing merlin-mediated contact inhibition of growth.

ABSTRACT: In normal tissues, strict control of tissue size is achieved by regulating cell numbers. The mechanism that controls total cell number is known as contact inhibition of growth and it depends on the NF2/Merlin pathway. Negative regulation of this pathway by deleterious mutations or by oncogenes results in cell transformation and tumor progression. Here we provide evidence that the CD43 sialomucin cooperates with oncogenic signals to promote cell transformation by abrogating the contact inhibition of growth through a molecular mechanism that involves AKT-dependent Merlin phosphorylation and degradation. Accordingly, inhibition of endogenous CD43 expression by RNA interference in lung, cervix and colon human cancer cells impaired tumor growth in vivo. These data underscore a previously unidentified role for CD43 in non-hematopoietic tumor progression.

SUBMITTER: Camacho-Concha N

PROVIDER: S-EPMC3832598 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

CD43 promotes cells transformation by preventing merlin-mediated contact inhibition of growth.

Camacho-Concha Nohemi N Olivos-Ortiz Amiel A Nuñez-Rivera Alfredo A Pedroza-Saavedra Adolfo A Gutierrez-Xicotencatl Lourdes L Rosenstein Yvonne Y Pedraza-Alva Gustavo G

PloS one 20131118 11

In normal tissues, strict control of tissue size is achieved by regulating cell numbers. The mechanism that controls total cell number is known as contact inhibition of growth and it depends on the NF2/Merlin pathway. Negative regulation of this pathway by deleterious mutations or by oncogenes results in cell transformation and tumor progression. Here we provide evidence that the CD43 sialomucin cooperates with oncogenic signals to promote cell transformation by abrogating the contact inhibition ...[more]

PMID: 24260485

Similar Datasets

Contact-dependent inhibition of EGFR signaling by Nf2/Merlin.

Project description:The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, is a membrane/cytoskeleton-associated protein that mediates contact-dependent inhibition of proliferation. Here we show that upon cell-cell contact Merlin coordinates the processes of adherens junction stabilization and negative regulation of epidermal growth factor receptor (EGFR) signaling by restraining the EGFR into a membrane compartment from which it can neither signal nor be internalized. In confluent Nf2(-/-) cells, EGFR activation persists, driving continued proliferation that is halted by specific EGFR inhibitors. These studies define a new mechanism of tumor suppression, provide mechanistic insight into the poorly understood phenomenon of contact-dependent inhibition of proliferation, and suggest a therapeutic strategy for NF2-mutant tumors.

| S-EPMC2064288 | biostudies-literature

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

Transcriptional control by Merlin of contact inhibition and tissue homeostasis

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-04-01 | GSE53501 | GEO

CD43-mediated IFN-? production by CD8+ T cells promotes abdominal aortic aneurysm in mice.

Project description:CD43 is a glycosylated surface protein abundantly expressed on lymphocytes. Its role in immune responses has been difficult to clearly establish, with evidence supporting both costimulatory and inhibitory functions. In addition, its contribution to disease pathogenesis remains elusive. Using a well-characterized murine model of elastase-induced abdominal aortic aneurysm (AAA) that recapitulates many key features of the human disease, we established that the presence of CD43 on T cells is required for AAA formation. Moreover, we found that IFN-?-producing CD8(+) T cells, but not CD4(+) T cells, promote the development of aneurysm by enhancing cellular apoptosis and matrix metalloprotease activity. Reconstitution with IFN-?-producing CD8(+) T cells or recombinant IFN-? promotes the aneurysm phenotype in CD43(-/-) mice, whereas IFN-? antagonism abrogates disease in wild-type animals. Furthermore, we showed that the presence of CD43 with an intact cytoplasmic domain capable of binding to ezrin-radixin-moesin cytoskeletal proteins is essential for optimal in vivo IFN-? production by T cells and aneurysm formation. We have thus identified a robust physiologic role for CD43 in a relevant animal model and established an important in vivo function for CD43-dependent regulation of IFN-? production. These results further suggest that IFN-? antagonism or selective blockade of CD43(+)CD8(+) T cell activities merits further investigation for immunotherapy in AAA.

| S-EPMC3647012 | biostudies-literature

ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth.

Project description:The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/-) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.

| S-EPMC3533536 | biostudies-literature

Bacterial contact-dependent growth inhibition.

Project description:Bacteria cooperate to form multicellular communities and compete against one another for environmental resources. Here, we review recent advances in the understanding of bacterial competition mediated by contact-dependent growth inhibition (CDI) systems. Different CDI+ bacteria deploy a variety of toxins to inhibit neighboring cells and protect themselves from autoinhibition by producing specific immunity proteins. The genes encoding CDI toxin-immunity protein pairs appear to be exchanged between cdi loci and are often associated with other toxin-delivery systems in diverse bacterial species. CDI also appears to facilitate cooperative behavior between kin, suggesting that these systems may have other roles beyond competition.

| S-EPMC3648609 | biostudies-literature

NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin.

Project description:The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane-cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell-cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact.

| S-EPMC4621825 | biostudies-other

Two Sides of the Coin: Ezrin/Radixin/Moesin and Merlin Control Membrane Structure and Contact Inhibition.

Project description:The merlin-ERM (ezrin, radixin, moesin) family of proteins plays a central role in linking the cellular membranes to the cortical actin cytoskeleton. Merlin regulates contact inhibition and is an integral part of cell-cell junctions, while ERM proteins, ezrin, radixin and moesin, assist in the formation and maintenance of specialized plasma membrane structures and membrane vesicle structures. These two protein families share a common evolutionary history, having arisen and separated via gene duplication near the origin of metazoa. During approximately 0.5 billion years of evolution, the merlin and ERM family proteins have maintained both sequence and structural conservation to an extraordinary level. Comparing crystal structures of merlin-ERM proteins and their complexes, a picture emerges of the merlin-ERM proteins acting as switchable interaction hubs, assembling protein complexes on cellular membranes and linking them to the actin cytoskeleton. Given the high level of structural conservation between the merlin and ERM family proteins we speculate that they may function together.

| S-EPMC6515277 | biostudies-literature

H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule.

Project description:Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic long noncoding RNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)-induced liver fibrosis, which was accompanied by the elevation of serum alanine aminotransferase, aspartate aminotransferase, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL versus null-BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19-BDL mice showed significant enrichment of CD3+??+, interleukin-4, and interleukin-17 producing CD4+ and CD8+ immune cell populations. H19 down-regulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1) but up-regulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)-box 9 expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription. H19RNA impeded ZEB1's inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19-induced fibrosis; the latter was also prevented in H19-/- mice. H19RNA was markedly induced by bile acids in mouse small cholangiocytes and to a lesser extent in mouse large cholangiocytes. The up-regulation of H19RNA and EpCAM correlated positively with the down-regulation of ZEB1 in primary sclerosing cholangitis and primary biliary cirrhosis liver specimens. CONCLUSION:The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway. (Hepatology 2017;66:1183-1196).

| S-EPMC5605402 | biostudies-literature

Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2.

Project description:Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) leads to liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the sphingosine kinase (SphK)1-dependent effect on liver fibrosis. The levels of expression and activity of SphK1 were significantly increased in fibrotic livers compared with the normal livers in human. SphK1 was coexpressed with a range of HSC/KC markers including desmin, α-smooth muscle actin (α-SMA) and F4/80 in fibrotic liver. Deficiency of SphK1 (SphK1-/- ) resulted in a marked amelioration of hepatic injury, including transaminase activities, histology, collagen deposition, α-SMA and inflammation, in CCl4 or bile duct ligation (BDL)-induced mice. Likewise, treatment with a specific inhibitor of SphK1, 5C, also significantly prevented liver injury and fibrosis in mice induced by CCl4 or BDL. In cellular levels, inhibition of SphK1 significantly blocked the activation and migration of HSCs and KCs. Moreover, SphK1 knockout in KCs reduced the secretion of CCL2, and SphK1 knockout in HSCs reduced C-C motif chemokine receptor 2 ([CCR2] CCL2 receptor) expression in HSCs. CCL2 in SphK1-/- mice was lower whereas microRNA-19b-3p in SphK1-/- mice was higher compared with wild-type (WT) mice. Furthermore, microRNA-19b-3p downregulated CCR2 in HSCs. The functional effect of SphK1 in HSCs on liver fibrosis was further strengthened by the results of animal experiments using a bone marrow transplantation (BMT) method. CONCLUSION:SphK1 has distinct roles in the activation of KCs and HSCs in liver fibrosis. Mechanistically, SphK1 in KCs mediates CCL2 secretion, and SphK1 in HSCs upregulates CCR2 by downregulation of miR-19b-3p. (Hepatology 2018).

| S-EPMC6174945 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data