Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis

A. Raafat; S. Lawson; S. Bargo; M. Klauzinska; L. Strizzi; A. S. Goldhar; K. Buono; D. Salomon; B. K. Vonderhaar; R. Callahan

doi:10.1038/onc.2008.379

Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis

A. Raafat, S. Lawson, S. Bargo, M. Klauzinska, L. Strizzi, A. S. Goldhar, K. Buono, D. Salomon, B. K. Vonderhaar, R. Callahan^*

^*Corresponding author for this work

Pathology

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

49 Scopus citations

Abstract

Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. We have conditionally ablated the Rbpj gene in the mammary glands of mice expressing whey acidic protein (Wap)-Int3. Interestingly, Rbpj knockout mice (Wap-Cre⁺/Rbpj^-/-/Wap-Int3) have normal mammary gland development, suggesting that the effect of endogenous Notch signaling on mammary gland development is complete by day 15 of pregnancy. RBP-J heterozygous (Wap-Cre⁺/Rbpj^-/+/Wap-Int3) and Rbpj control (Rbpj ^flox/flox/Wap-Int3) mice are phenotypically the same as Wap-Int3 mice with respect to mammary gland development and tumorigenesis. In addition, the Wap-Cre⁺/Rbpj^-/-/Wap-Int3-knockout mice also developed mammary tumors at a frequency similar to Rbpj heterozygous and Wap-Int3 control mice but with a slightly longer latency. Thus, the effect on mammary gland development is dependent on the interaction of the Notch ICD with the transcription repressor/activator Rbpj, and Notch-induced mammary tumor development is independent of this interaction.

Original language	English (US)
Pages (from-to)	219-230
Number of pages	12
Journal	Oncogene
Volume	28
Issue number	2
DOIs	https://doi.org/10.1038/onc.2008.379
State	Published - Jan 15 2009

Funding

The Rbpjflox/flox mice were kindly provided by Dr Tasuku Honjo, Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan, and the WAP-Cre mice were kindly provided by Dr Lothar Hennighausen, Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Keywords

Int3
RBP-J
Tumorigenesis

ASJC Scopus subject areas

Genetics
Molecular Biology
Cancer Research

UN SDGs

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

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10.1038/onc.2008.379

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@article{d4b20bd0f20a4121808cb6cd3facbaf6,

title = "Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis",

abstract = "Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. We have conditionally ablated the Rbpj gene in the mammary glands of mice expressing whey acidic protein (Wap)-Int3. Interestingly, Rbpj knockout mice (Wap-Cre+/Rbpj-/-/Wap-Int3) have normal mammary gland development, suggesting that the effect of endogenous Notch signaling on mammary gland development is complete by day 15 of pregnancy. RBP-J heterozygous (Wap-Cre+/Rbpj-/+/Wap-Int3) and Rbpj control (Rbpj flox/flox/Wap-Int3) mice are phenotypically the same as Wap-Int3 mice with respect to mammary gland development and tumorigenesis. In addition, the Wap-Cre+/Rbpj-/-/Wap-Int3-knockout mice also developed mammary tumors at a frequency similar to Rbpj heterozygous and Wap-Int3 control mice but with a slightly longer latency. Thus, the effect on mammary gland development is dependent on the interaction of the Notch ICD with the transcription repressor/activator Rbpj, and Notch-induced mammary tumor development is independent of this interaction.",

keywords = "Int3, RBP-J, Tumorigenesis",

author = "A. Raafat and S. Lawson and S. Bargo and M. Klauzinska and L. Strizzi and Goldhar, {A. S.} and K. Buono and D. Salomon and Vonderhaar, {B. K.} and R. Callahan",

note = "Funding Information: The Rbpjflox/flox mice were kindly provided by Dr Tasuku Honjo, Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan, and the WAP-Cre mice were kindly provided by Dr Lothar Hennighausen, Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.",

year = "2009",

month = jan,

day = "15",

doi = "10.1038/onc.2008.379",

language = "English (US)",

volume = "28",

pages = "219--230",

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T1 - Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis

AU - Raafat, A.

AU - Lawson, S.

AU - Bargo, S.

AU - Klauzinska, M.

AU - Strizzi, L.

AU - Goldhar, A. S.

AU - Buono, K.

AU - Salomon, D.

AU - Vonderhaar, B. K.

AU - Callahan, R.

N1 - Funding Information: The Rbpjflox/flox mice were kindly provided by Dr Tasuku Honjo, Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan, and the WAP-Cre mice were kindly provided by Dr Lothar Hennighausen, Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

PY - 2009/1/15

Y1 - 2009/1/15

N2 - Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. We have conditionally ablated the Rbpj gene in the mammary glands of mice expressing whey acidic protein (Wap)-Int3. Interestingly, Rbpj knockout mice (Wap-Cre+/Rbpj-/-/Wap-Int3) have normal mammary gland development, suggesting that the effect of endogenous Notch signaling on mammary gland development is complete by day 15 of pregnancy. RBP-J heterozygous (Wap-Cre+/Rbpj-/+/Wap-Int3) and Rbpj control (Rbpj flox/flox/Wap-Int3) mice are phenotypically the same as Wap-Int3 mice with respect to mammary gland development and tumorigenesis. In addition, the Wap-Cre+/Rbpj-/-/Wap-Int3-knockout mice also developed mammary tumors at a frequency similar to Rbpj heterozygous and Wap-Int3 control mice but with a slightly longer latency. Thus, the effect on mammary gland development is dependent on the interaction of the Notch ICD with the transcription repressor/activator Rbpj, and Notch-induced mammary tumor development is independent of this interaction.

AB - Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. We have conditionally ablated the Rbpj gene in the mammary glands of mice expressing whey acidic protein (Wap)-Int3. Interestingly, Rbpj knockout mice (Wap-Cre+/Rbpj-/-/Wap-Int3) have normal mammary gland development, suggesting that the effect of endogenous Notch signaling on mammary gland development is complete by day 15 of pregnancy. RBP-J heterozygous (Wap-Cre+/Rbpj-/+/Wap-Int3) and Rbpj control (Rbpj flox/flox/Wap-Int3) mice are phenotypically the same as Wap-Int3 mice with respect to mammary gland development and tumorigenesis. In addition, the Wap-Cre+/Rbpj-/-/Wap-Int3-knockout mice also developed mammary tumors at a frequency similar to Rbpj heterozygous and Wap-Int3 control mice but with a slightly longer latency. Thus, the effect on mammary gland development is dependent on the interaction of the Notch ICD with the transcription repressor/activator Rbpj, and Notch-induced mammary tumor development is independent of this interaction.

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Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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