Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells

Sanne Weijzen; Paola Rizzo; Mike Braid; Radhika Vaishnav; Suzanne M. Jonkheer; Andrei Zlobin; Barbara A. Osborne; Sridevi Gottipati; Jon C. Aster; William C. Hahn; Michael Rudolf; Kalliopi Siziopikou; W. Martin Kast; Lucio Miele

doi:10.1038/nm754

Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells

Sanne Weijzen, Paola Rizzo, Mike Braid, Radhika Vaishnav, Suzanne M. Jonkheer, Andrei Zlobin, Barbara A. Osborne, Sridevi Gottipati, Jon C. Aster, William C. Hahn, Michael Rudolf, Kalliopi Siziopikou, W. Martin Kast, Lucio Miele

Pathology

Research output: Contribution to journal › Article › peer-review

482 Scopus citations

Abstract

Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wildtype Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.

Original language	English (US)
Pages (from-to)	979-986
Number of pages	8
Journal	Nature Medicine
Volume	8
Issue number	9
DOIs	https://doi.org/10.1038/nm754
State	Published - Sep 2002

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm754

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@article{d08f960afaf4410e91a9a85a189552ca,

title = "Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells",

abstract = "Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wildtype Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.",

author = "Sanne Weijzen and Paola Rizzo and Mike Braid and Radhika Vaishnav and Jonkheer, {Suzanne M.} and Andrei Zlobin and Osborne, {Barbara A.} and Sridevi Gottipati and Aster, {Jon C.} and Hahn, {William C.} and Michael Rudolf and Kalliopi Siziopikou and Kast, {W. Martin} and Lucio Miele",

note = "Funding Information: Acknowledgments We thank T. Kadesch for the CBF-1 reporter plasmid; L. Heasley for the constitutively active MKK6 plasmid; B. Nickoloff for the dominant-negative mutant Ras construct; J.L. Bos for the constitutively active Rlf-CAAX plasmid; T. Golde for the γ-secretase inhibitor; and M.P. Velders, B. Nickoloff and V. Chaturvedi for helpful suggestions and critical reading of this manuscript. This work was supported by the Illinois Department of Public Health and NIH RO1 CA 84065/01 (to L.M.), NIH RO1 CA/AI 78399 (to W.M.K.), NIH RO1 A47922 (to B.A.O.), and a Doris Duke Charitable Fund Clinical Scientist Award (to W.C.H.).",

year = "2002",

month = sep,

doi = "10.1038/nm754",

language = "English (US)",

volume = "8",

pages = "979--986",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

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T1 - Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells

AU - Weijzen, Sanne

AU - Rizzo, Paola

AU - Braid, Mike

AU - Vaishnav, Radhika

AU - Jonkheer, Suzanne M.

AU - Zlobin, Andrei

AU - Osborne, Barbara A.

AU - Gottipati, Sridevi

AU - Aster, Jon C.

AU - Hahn, William C.

AU - Rudolf, Michael

AU - Siziopikou, Kalliopi

AU - Kast, W. Martin

AU - Miele, Lucio

N1 - Funding Information: Acknowledgments We thank T. Kadesch for the CBF-1 reporter plasmid; L. Heasley for the constitutively active MKK6 plasmid; B. Nickoloff for the dominant-negative mutant Ras construct; J.L. Bos for the constitutively active Rlf-CAAX plasmid; T. Golde for the γ-secretase inhibitor; and M.P. Velders, B. Nickoloff and V. Chaturvedi for helpful suggestions and critical reading of this manuscript. This work was supported by the Illinois Department of Public Health and NIH RO1 CA 84065/01 (to L.M.), NIH RO1 CA/AI 78399 (to W.M.K.), NIH RO1 A47922 (to B.A.O.), and a Doris Duke Charitable Fund Clinical Scientist Award (to W.C.H.).

PY - 2002/9

Y1 - 2002/9

N2 - Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wildtype Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.

AB - Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wildtype Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wildtype Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.

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Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells

Abstract

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