Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis.
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.
Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
A
A
Raafat
S
S
Lawson
S
S
Bargo
M
M
Klauzinska
L
L
Strizzi
A S
AS
Goldhar
K
K
Buono
D
D
Salomon
B K
BK
Vonderhaar
R
R
Callahan
D000231:Adenocarcinoma, Papillary / Q000235:genetics / Q000473:pathology; D000362:Agar; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002472:Cell Transformation, Viral / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000196:embryology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008894:Milk Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics; D020079:Terminal Repeat Sequences / Q000235:genetics; D000072056:Transcription Factor HES-1; D014407:Tumor Cells, Cultured / Q000166:cytology
D000362:Agar; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D008894:Milk Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; C485778:Hey2 protein, mouse; C024471:whey acidic proteins; C073572:Notch4 protein, mouse