scribblemutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs

Leong, Gregory R; Goulding, Karen; Amin, Nancy; Richardson, Helena E.; Brumby, Anthony M.

doi:10.1186/1741-7007-7-62

Cited by 87 publications

(180 citation statements)

References 45 publications

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“…Interestingly, the neoplastic phenotype of scrib − cells depends on their cellular environment. When scrib − cells are produced in patches (clones) of mutant cells that are surrounded by normal cells, they do not hyperproliferate, remain small, and eventually are eliminated (2)(3)(4)(5)(6)(7)(11)(12)(13). Similar effects are observed for lgl − and dlg − clones, although they may not be eliminated very efficiently (11,14,15).…”

supporting

confidence: 52%

“…Similar effects are observed for lgl − and dlg − clones, although they may not be eliminated very efficiently (11,14,15). Thus, the presence of wild-type cells prevents scrib − , lgl − , and dlg − cells from manifesting their tumorigenic potential (2)(3)(4)(5)(6)(7)(11)(12)(13)(14)(15). Several groups have shown that the JNK stress-response pathway is activated in scrib − clones, leading to engulfment and death or extrusion of mutant cells from the epithelium (2-4, 6, 11, 16).…”

supporting

confidence: 50%

“…Notably, scrib − cells that cannot activate JNK still showed defects in photoreceptor differentiation, observed through ELAV expression, and in cell polarity, observed through anti-Patj staining, forming multilayered structures of tumorigenic cells ( Fig. 1 H and I) (12). These data show that scrib − cells have the potential to hyperproliferate and in genetic mosaics this potential is counteracted by JNK activity (2, 3).…”

Section: Resultsmentioning

confidence: 69%

“…1 D and G and Fig. S1D) (2)(3)(4)12). In addition to surviving, these clones hyperproliferated, as revealed by an excess of BrdU-incorporating cells in mutant clones, in contrast to scrib − clones with normal JNK activity, which did not grow and remained small (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1 E-G and Fig. S2 A-F) (12). Therefore, in addition to triggering apoptosis, JNK signaling counteracts the potential of scrib − cells to hyperproliferate (2,3).…”

Section: Resultsmentioning

confidence: 99%

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Tumor suppression by cell competition through regulation of the Hippo pathway

Chen

Schroeder

Kango‐Singh

et al. 2011

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

168

249

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Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene scribble ( scrib ) are eliminated from Drosophila imaginal discs. When all cells in imaginal discs are mutant for scrib, they hyperactivate the Hippo pathway effector Yorkie (Yki), which drives growth of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, the scrib − cells do not overproliferate and eventually undergo apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how scrib − cells are prevented from overproliferating. We report that cell competition between scrib − and wild-type cells prevents hyperproliferation by suppressing Yki activity in scrib − cells. Suppressing Yki activation is critical for scrib − clone elimination by cell competition, and experimental elevation of Yki activity in scrib − cells is sufficient to fuel their neoplastic growth. Thus, cell competition acts as a tumor-suppressing mechanism by regulating the Hippo pathway in scrib − cells.

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supporting

confidence: 52%

supporting

confidence: 50%

Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

“…1 E-G and Fig. S2 A-F) (12). Therefore, in addition to triggering apoptosis, JNK signaling counteracts the potential of scrib − cells to hyperproliferate (2,3).…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Tumor suppression by cell competition through regulation of the Hippo pathway

Chen

Schroeder

Kango‐Singh

et al. 2011

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

168

249

View full text Add to dashboard Cite

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Modelling Cancer in Drosophila : The Next Generation

Cheng

Parsons

Richardson

2013

Encyclopedia of Life Sciences

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Drosophila melanogaster , the vinegar fly, has been utilised as a genetic amenable model organism for more than 100 years. In recent years, its use in modelling human cancer has been greatly expanding. In this article, an update of the recent advances in Drosophila research towards understanding cancer development is provided. Genetic analysis in Drosophila has provided considerable insight into the mechanisms controlling tissue growth and cell invasion/metastasis during tumourigenesis, as well as the importance of stem cells in tissue regeneration and cancer, and how genes cooperate in tumourigenesis. Several evolutionarily conserved signalling pathways are emerging as playing key roles in many of these processes, including the Jun kinase, Notch, Wnt, Jak/Stat and the Hippo tissue growth control pathway. Drosophila has also been specifically utilised to model certain human cancers, by expression of the human versions of cancer‐causing genes, including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia. Finally, the use of Drosophila as a vehicle for anticancer drug discovery is beginning to make an important impact in combating human cancer. Key Concepts: Drosophila is a useful system for modelling human cancer due to the high conservation of critical cancer‐causing genes between humans and flies. Many signalling pathways contribute to tissue growth; however, the Hippo growth control pathway is emerging as playing a major role. The Jun kinase signalling pathway plays a context‐dependent role in invasion/metastasis. Cell polarity and differentiation factors play important roles in controlling the behaviour of stem cells, which can be usurped in cancer. Cell competition mechanisms are important in removing damaged cells, and the perturbation of this control contributes to tumourigenesis. Cancer is a cooperative process and Drosophila research has revealed many cooperating oncogenes and tumour suppressors. Drosophila provides a useful model system to investigate specific human cancers including multiple endocrine neoplasia type 2, glioblastoma and acute myeloid leukaemia. Drosophila can be utilised to screen for anticancer drugs.

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Deltex cooperates with TRAF6 to promote apoptosis and cell migration through Eiger‐independent JNK activation in Drosophila

Sharma

Mutsuddi

Mukherjee

2020

Cell Biology International

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JNK signaling is a highly conserved signaling pathway that regulates a broad spectrum of cellular processes including cell proliferation, migration, and apoptosis. In Drosophila, JNK signaling is activated by binding of the tumor necrosis factor (TNF) Eiger to its receptor Wengen, and a conserved signaling cascade operates that culminates into activation of dual phosphatase Puckered thereby triggering apoptosis. The tumor necrosis factor receptor (TNFR) associated factor 6 (TRAF6) is an adaptor protein, which transduces the signal from TNFRs and Toll‐like receptor/interleukin‐1 receptor superfamily to induce a wide spectrum of cellular responses. TRAF6 also acts as the adaptor protein that mediates Eiger/JNK signaling in Drosophila. In a genetic interaction study, deltex (Dx) was identified as a novel interactor of TRAF6. Dx is well known to regulate Notch signaling in a context‐dependent manner. Our data suggest that combinatorial action of Dx and TRAF6 enhances the Dx‐induced wing nicking phenotype by inducing caspase‐mediated cell death. Co‐expression of Dx and TRAF6 also results in enhanced invasive behavior and perturbs the normal morphology of cells. The cooperative action of Dx and TRAF6 is attributed to JNK activation, which also leads to ectopic wingless (Wg) and decapentaplegic (Dpp) expression. Our results also reveal that the endocytic pathway component Rab7 may play a pivotal role in the regulation of Dx–TRAF6‐mediated activation of JNK signaling. Here, we present the fact that Dx and TRAF6 together activate JNK signaling in an Eiger‐independent mechanism.

show abstract

scribblemutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs

Cited by 87 publications

References 45 publications

Tumor suppression by cell competition through regulation of the Hippo pathway

Tumor suppression by cell competition through regulation of the Hippo pathway

Modelling Cancer in Drosophila : The Next Generation

Deltex cooperates with TRAF6 to promote apoptosis and cell migration through Eiger‐independent JNK activation in Drosophila

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