Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think

Lobry, Camille; Oh, Phil; Aifantis, Iannis

doi:10.1084/jem.20111855

Cited by 323 publications

(250 citation statements)

References 33 publications

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“…Interestingly, Notch signaling previously has been reported to function as both a tumor suppressor and an oncogene (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The dependency of Notch1 function in cancer may be tissue specific and context dependent (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Loss-offunction mutations in Notch receptors support their tumor-suppressive role in multiple malignances, including bladder cancer and squamous cell carcinoma (22)(23)(24).…”

Section: Significancementioning

confidence: 99%

“…Constitutive activation of the Notch receptors through gene rearrangements or mutations leads to Notch receptors' oncogenic function in 55-60% of patients with T-cell acute lymphoblastic leukemia (26,27). An oncogenic role of Notch1 also has been demonstrated in chronic lymphocytic leukemia and in solid tumors such as lung adenocarcinoma and others (28)(29)(30)(31). Mutations within Notch1 receptor are rare (3% frequency) in metastatic prostate cancer (32,33).…”

Section: Significancementioning

confidence: 99%

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Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Stoyanova

Riedinger

Lin

et al. 2016

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

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Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer.

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Stoyanova

Riedinger

Lin

et al. 2016

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

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“…The broad range of processes that require Notch signaling is reflected by the variety of human diseases that result from mutations in components of the Notch signaling pathway (Koch and Radtke, 2010;Lobry et al, 2011). The mammalian genome encodes for 4 Notch receptors (Notch1-4) that can be activated by binding of ligands that belong to the Serratelike (Jagged1 and Jagged2) or Delta-like (DLL1, DLL3, and DLL4) families (Kopan and Ilagan, 2009).…”

mentioning

confidence: 99%

Specific Notch receptor–ligand interactions control human TCR-ab/gd development by inducing differential Notch signal strength

Walle¹,

Waegemans²,

Medts³

et al. 2013

J Cell Biol

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“…4,7,61 Comparable NOTCH1 mutations are also found in B-cell lymphomas 62 and both activation and inactivation of the pathway have been identified in hematopoietic and non-hematopoietic diseases. 63 As with T-cell acute lymphoblastic leukemia, mutations inactivating the FBXW7 gene, which codes normal feedback control of Notch signaling (which also control CMYC stability 64 ), are also observed in CLL. In some series, mutations of NOTCH1 and FBXW7 are associated with the presence of trisomy 12 and the nonmutated status of the hypervariable regions of immunoglobulin genes.…”

Section: Other Novel Mutations In Lymphomasmentioning

confidence: 99%

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

et al. 2012

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Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. Leukemia (2012Leukemia ( ) 26, 2027Leukemia ( -2031 doi:10.1038/leu.2012 Keywords: CLL; MDS; mutations; spliceosome INTRODUCTIONIn a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab). [1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45-85% of patients with MDS; 1 the majority constituted missense mutations located in restricted regions of proteins.A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19 þ and CD5 þ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts). [4][5][6][7] In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected. 4,6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms. 4 The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing. 8 The involvement of oncogenes in RNA processing h...

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Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think

Abstract: Aifantis and colleagues examine the conflicting roles of Notch signaling in various cancer types.

Cited by 323 publications

References 33 publications

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Specific Notch receptor–ligand interactions control human TCR-ab/gd development by inducing differential Notch signal strength

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

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