The dASPP-dRASSF8 Complex Regulates Cell-Cell Adhesion during Drosophila Retinal Morphogenesis

Langton, Paul F.; Colombani, Julien; Chan, Eunice HoYee; Wepf, Alexander; Gstaiger, Matthias; Tapon, Nicolas

doi:10.1016/j.cub.2009.10.027

Cited by 44 publications

(61 citation statements)

References 34 publications

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“…This suggests that the two genes have diverged in their function. In Drosophila, there is one gene that is related to RASSF7 and RASSF8, and it appears that the function of this gene is more similar to RASSF8 than RASSF7 (Langton et al, 2009). Langton et al have recently described the role of Drosophila dASPPdRASSF8 in regulating cell-cell adhesion during Drosophila retinal morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

et al. 2010

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The Ras-assocation domain family (RASSF) of tumor suppressor proteins until recently contained six proteins named RASSF1-6. Recently, four novel family members, RASSF7-10, have been identified by homology searches for RA-domain-containing proteins. These additional RASSF members are divergent and structurally distinct from RASSF1-6, containing an N-terminal RA domain and lacking the Sav/RASSF/Hpo (SARAH) domain. Here, we show that RASSF8 is ubiquitously expressed throughout the murine embryo and in normal human adult tissues. Functionally, RNAi-mediated knockdown of RASSF8 in non-small-cell lung cancer (NSCLC) cell lines, increased anchorage-independent growth in soft agar and enhanced tumor growth in severe combined immunodeficiency (SCID) mice. Furthermore, EdU staining of RASSF8-depleted cells showed growth suppression in a manner dependent on contact inhibition. We show that endogenous RASSF8 is not only found in the nucleus, but is also membrane associated at sites of cell-cell adhesion, co-localizing with the adherens junction (AJ) component b-catenin and binding to E-cadherin. Following RASSF8 depletion in two different lung cancer cell lines using alternative small interfering RNA (siRNA) sequences, we show that AJs are destabilized and E-cadherin is lost from the cell membrane. The AJ components b-catenin and p65 are also lost from sites of cell-cell contact and are relocalized to the nucleus with a concomitant increase in b-catenin-dependent and nuclear factorjB (NF-jB)-dependent signaling following RASSF8 depletion. RASSF8 may also be required to maintain actin -cytoskeletal organization since immunofluorescence analysis shows a striking disorganization of the actincytoskeleton following RASSF8 depletion. Accordingly, scratch wound healing studies show increased cellular migration in RASSF8-deficient cells. These results implicate RASSF8 as a tumor suppressor gene that is essential for maintaining AJs function in epithelial cells and have a role in epithelial cell migration.

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Section: Discussionmentioning

confidence: 99%

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

et al. 2010

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“…While there are 10 RASSF genes in human cells, the Drosophila genome contains only two orthologs, known as dRASSF and dRASSF8 (53,60). Of these genes, dRASSF is most similar to the C-terminal RASSF1-6, and most similar to RASSF4 within the Ras-association and SARAH domains.…”

Section: Discussionmentioning

confidence: 99%

Alveolar rhabdomyosarcoma–associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression

et al. 2013

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Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the paired box 3-forkhead box protein O1 (PAX3-FOXO1) fusion oncogene. Despite its discovery nearly two decades ago, the mechanisms by which PAX3-FOXO1 drives tumor development are not well characterized. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence checkpoints. We have now found that this bypass occurs in part through PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member. RASSF4 expression was upregulated in PAX3-FOXO1-positive aRMS cell lines and tumors. Enhanced RASSF4 expression promoted cell cycle progression, senescence evasion, and tumorigenesis through inhibition of the Hippo pathway tumor suppressor MST1. We also found that the downstream Hippo pathway target Yes-associated protein 1 (YAP), which is ordinarily restrained by Hippo signaling, was upregulated in RMS tumors. These data suggest that Hippo pathway dysfunction promotes RMS. This work provides evidence for Hippo pathway suppression in aRMS and demonstrates a progrowth role for RASSF4. Additionally, we identify a mechanism used by PAX3-FOXO1 to inhibit MST1 signaling and promote tumorigenesis in aRMS. Introduction Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Over the past 30 years, clinical trials in North America, Europe, and Australia have identified superior treatment strategies leading to the improved survival of discrete groups of RMS patients. A distinctly worse outcome is encountered for patients with the alveolar histologic variant of RMS (aRMS), who have a 5-year survival rate of less than 50% (1). Even more dismal is the survival for those whose tumors express the signature paired box 3-forkhead box protein O1 (PAX3-FOXO1) fusion gene; in the metastatic setting, their survival rate at 4 years is less than 10% (2). Although PAX3-FOXO1 (and the related fusion protein PAX7-FOXO1) was identified in the 1990s (3-5) and intensely studied in terms of its regulation, downstream targets, and cellular phenotypic effects, a unified understanding of how the fusion gene and its resulting oncoprotein contribute so profoundly to aRMS tumorigenesis remains obscure.

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“…In mammalian cells, ASPP2 associates with Par-3, a complex crucial for the formation and localization of the apical-junctional complex (AJC). ASPP2-depleted cells are defective in the formation of tight junctions and acquire a migratory phenotype (29,(37)(38)(39). Thus, ASPP2 may have a dual role.…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

Buti

Spooner

Veen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

212

166

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Type I strains of Helicobacter pylori (Hp) possess a pathogenicity island, cag , that encodes the effector protein cytotoxin-associated gene A (CagA) and a type four secretion system. After translocation into the host cell, CagA affects cell shape, increases cell motility, abrogates junctional activity, and promotes an epithelial to mesenchymal transition-like phenotype. Transgenic expression of CagA enhances gastrointestinal and intestinal carcinomas as well as myeloid and B-cell lymphomas in mice, but the mechanism of the induced cancer formation is not fully understood. Here, we show that CagA subverts the tumor suppressor function of apoptosis-stimulating protein of p53 (ASPP2). Delivery of CagA inside the host results in its association with ASPP2. After this interaction, ASPP2 recruits its natural target p53 and inhibits its apoptotic function. CagA leads to enhanced degradation of p53 and thereby, down-regulates its activity in an ASPP2-dependent manner. Finally, Hp-infected cells treated with the p53-activating drug Doxorubicin are more resistant to apoptosis than uninfected cells, an effect that requires ASPP2. The interaction between CagA and ASPP2 and the consequent degradation of p53 are examples of a bacterial protein that subverts the p53 tumor suppressor pathway in a manner similar to DNA tumor viruses. This finding may contribute to the understanding of the increased risk of gastric cancer in patients infected with Hp CagA+ strains.

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The dASPP-dRASSF8 Complex Regulates Cell-Cell Adhesion during Drosophila Retinal Morphogenesis

Cited by 44 publications

References 34 publications

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

Alveolar rhabdomyosarcoma–associated PAX3-FOXO1 promotes tumorigenesis via Hippo pathway suppression

Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host

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