Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene

Development ◽  
1996 ◽  
Vol 122 (7) ◽  
pp. 2251-2259 ◽  
Author(s):  
H. Uyttendaele ◽  
G. Marazzi ◽  
G. Wu ◽  
Q. Yan ◽  
D. Sassoon ◽  
...  
Keyword(s):  
Adult Life ◽  
Cdna Clones ◽  
Mouse Development ◽  
Intracellular Domain ◽  
Notch Protein ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
Notch Gene ◽  
Epidermal Growth ◽  
Coding Potential

The int-3 oncogene was identified as a frequent target in Mouse Mammary Tumor Virus (MMTV)-induced mammary carcinomas and encodes the intracellular domain of a novel mouse Notch gene. To investigate the role of the int-3 proto-oncogene in mouse development and carcinogenesis, we isolated cDNA clones corresponding to the entire coding potential of the int-3 proto-oncogene. We propose to name this gene Notch4 and reserve the int-3 nomenclature for references to the oncogenic form. The deduced amino acid sequence of Notch4 contains conserved motifs found in Notch proteins; however Notch4 has fewer epidermal growth factor (EGF)-like repeats and a shorter intracellular domain than other mouse Notch homologues. Comparison of the coding potential of the int-3 gene to that of Notch4 suggests that loss of the extracellular domain of Notch4 leads to constitutive activation of this murine Notch protein. In situ hybridization revealed that Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life. Truncated Notch4 transcripts were detected in post-meiotic male germ cells. The distinct Notch4 protein features and its restricted expression pattern suggests a specific role for Notch4 during development of vertebrate endothelium.

scholarly journals The Oncoprotein Kinase Chaperone CDC37 Functions as an Oncogene in Mice and Collaborates with Both c-mycand Cyclin D1 in Transformation of Multiple Tissues

2000 ◽  
Vol 20 (12) ◽  
pp. 4462-4473 ◽  
Author(s):  
Lilia Stepanova ◽  
Milton Finegold ◽  
Franco DeMayo ◽  
Emmett V. Schmidt ◽  
J. Wade Harper
Keyword(s):  
Mammary Gland ◽  
Cyclin D1 ◽  
Cell Transformation ◽  
Mouse Development ◽  
Positive Role ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
Rate Limiting ◽  
In Cells

ABSTRACT CDC37 encodes a 50-kDa protein that targets intrinsically unstable oncoprotein kinases including Cdk4, Raf-1, and v-src to the molecular chaperone Hsp90, an interaction that is thought to be important for the establishment of signaling pathways.CDC37 is required for proliferation in budding yeast and is coexpressed with cyclin D1 in proliferative zones during mouse development, a finding consistent with a positive role in cell proliferation. CDC37 expression may not only be required to support proliferation in cells that are developmentally programmed to proliferate but may also be required in cells that are inappropriately induced to initiate proliferation by oncogenes. Here we report that mouse mammary tumor virus (MMTV)-CDC37 transgenic mice develop mammary gland tumors at a rate comparable to that observed previously in MMTV-cyclin D1 mice. Moreover, CDC37 was found to collaborate with MMTV–c-myc in the transformation of multiple tissues, including mammary and salivary glands in females and testis in males, and also collaborates with cyclin D1 to transform the female mammary gland. These data indicate that CDC37can function as an oncogene in mice and suggests that the establishment of protein kinase pathways mediated by Cdc37-Hsp90 can be a rate-limiting event in epithelial cell transformation.

scholarly journals Mice Lacking the Metalloprotease-Disintegrin MDC9 (ADAM9) Have No Evident Major Abnormalities during Development or Adult Life

2002 ◽  
Vol 22 (5) ◽  
pp. 1537-1544 ◽  
Author(s):  
Gisela Weskamp ◽  
Hui Cai ◽  
Thomas A. Brodie ◽  
Shigeki Higashyama ◽  
Katia Manova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hippocampal Neurons ◽  
Adult Life ◽  
Cleavage Product ◽  
Heparin Binding ◽  
Wild Type ◽  
Mouse Development ◽  
Catalytically Active ◽  
Epidermal Growth

ABSTRACT MDC9 (ADAM9/meltrin γ) is a widely expressed and catalytically active metalloprotease-disintegrin protein that has been implicated in the ectodomain cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and as an α secretase for the amyloid precursor protein. In this study, we evaluated the expression of MDC9 during development and generated mice lacking MDC9 (mdc9 −/− mice) to learn more about the function of this protein during development and in adults. During mouse development, MDC9 mRNA is ubiquitously expressed, with particularly high expression levels in the developing mesenchyme, heart and brain. Despite the ubiquitous expression of MDC9, mdc9 −/− mice appear to develop normally, are viable and fertile, and do not have any major pathological phenotypes compared to wild-type mice. Constitutive and stimulated ectodomain shedding of HB-EGF is comparable in embryonic fibroblasts isolated from mdc9 −/− and wild-type mice, arguing against an essential role of MDC9 in HB-EGF shedding in these cells. Furthermore, there were no differences in the production of the APP α and γ secretase cleavage product (p3) and of β- and γ-secretase cleavage product (Aβ) in cultured hippocampal neurons from mdc9 −/− or wild-type mice, arguing against an essential major role of MDC9 as an α-secretase in mice. Further studies, including functional challenges and an evaluation of potential compensation by, or redundancy with, other members of the ADAM family or perhaps even with other molecules will be necessary to uncover physiologically relevant functions for MDC9 in mice.

scholarly journals Modifications of the notch function by Abruptex mutations in Drosophila melanogaster.

Genetics ◽  
1994 ◽  
Vol 136 (1) ◽  
pp. 183-194 ◽  
Author(s):  
J F de Celis ◽  
A Garcia-Bellido
Keyword(s):  
Transmembrane Protein ◽  
Extracellular Domain ◽  
Cell Fates ◽  
Notch Protein ◽  
Protein Functions ◽  
Notch Gene ◽  
Epidermal Growth ◽  
Notch Locus ◽  
Notch Ligands ◽  
Notch Activation

Abstract The function of the Notch gene is required in cell interactions defining alternative cell fates in several developmental processes. The Notch gene encodes a transmembrane protein with 36 epidermal growth factor (EGF)-like repeats in its extracellular domain. This protein functions as a receptor that interacts with other transmembrane proteins, such as Serrate and Delta, which also have EGF repeats in their extracellular domain. The Abruptex mutations of the Notch locus are associated with amino acid substitutions in the EGF repeats 24-29 of the Notch protein. We have studied, in genetic combinations, the modifications of Notch function caused by Abruptex mutations. These mutations lead to phenotypes which are opposite to those caused by Notch deletions. The Abruptex phenotypes are modified by the presence of mutations in other loci, in particular in the genes Serrate and Delta as well as Hairless, and groucho. The results suggest that all Abruptex mutations cause stronger than normal Notch activation by the Delta protein. Some Abruptex alleles also display an insufficiency of N function. Abruptex alleles which produce stronger enhancement of Notch activation also display stronger Notch insufficiency. This insufficiency could be due to reduced ability of Abruptex proteins to interact with Notch ligands and/or to form functional Notch dimers.

scholarly journals Intracisternal Type A Particle-Mediated Activation of the Notch4/int3 Gene in a Mouse Mammary Tumor: Generation of Truncated Notch4/int3 mRNAs by Retroviral Splicing Events

1999 ◽  
Vol 73 (6) ◽  
pp. 5166-5171 ◽  
Author(s):  
Jong-Seo Lee ◽  
Tatsuya Haruna ◽  
Akinori Ishimoto ◽  
Tasuku Honjo ◽  
Shin-ichi Yanagawa
Keyword(s):  
Mammary Tumor ◽  
Type A ◽  
Mammary Epithelial ◽  
Epithelial Cell Line ◽  
Mammary Epithelial Cell Line ◽  
Extra Copy ◽  
Mammary Tumor Virus ◽  
Intracellular Domain ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

ABSTRACT The int3 oncogene was discovered as a frequent target in mouse mammary tumor virus-induced mammary tumors and encodes the intracellular domain of a Notch4/int3 protein. In one spontaneous mammary tumor, no. 9, that developed in a BALB/c mouse, we have found an insertion of a 1.2-kb sequence, consisting of a 5′ long terminal repeat and gag sequences of an intracisternal type A particle (IAP) as well as an extra copy of the Notch4/int3genomic sequences containing exons 23 and 24, into the intron between exons 24 and 25 of the Notch4/int3 gene. In this tumor, unique splicing events between the IAP and the Notch4/int3sequences generated two types of IAP-Notch4/int3 fusion transcripts encoding two different portions of the intracellular domain of Notch4/int3 proteins: one with a RAM domain and the other without. Interestingly, these two proteins showed different subcellular localizations in a mouse mammary epithelial cell line, HC-11.

Electron Microscopy of the Nucleic Acid of Mouse Mammary Tumor Virus

1968 ◽  
Vol 26 ◽  
pp. 22-23
Author(s):  
N. H. Sarkar ◽  
Dan H. Moore
Keyword(s):  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Ammonium Acetate ◽  
Dry Weight ◽  
Mouse Tumor ◽  
Mammary Tumor Virus ◽  
Rna Molecules ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
The Subject

Mouse mammary tumor virus (MTV) is believed to contain about 0.8% single stranded ribonucleic acid (RNA). This value of RNA content was estimated on a dry weight basis. The subject of this report is an attempt to visualize the RNA molecules of MTV particles.MTV particles were isolated from RIII mouse (tumor incidence approximately 80%) milk according to the method described by Lyons and Moore. Purified virions from 5 ml of milk were finally suspended in 0.2 ml of PBS, pH 7.4 and was mixed with an equal volume of pronase (5 mg/ml). This mixture was incubated at 37°C for an hour. RNA was extracted three times using freshly prepared cold phenol. It was then treated three times with cold ethyl ether to remove any trace of phenol. The RNA thus extracted was divided into two parts. One part was diluted four fold with 8M urea to avoid aggregation of the molecules. The other part was left untreated. Both samples were then mixed with an equal volume of 1M ammonium acetate, adjusted to pH 8.0 with NH3 containing chymotrypsin at a concentration of 0.01%.

Electron Immunochemical Labeling of Ultrathin Sections of Murine Tumor Viruses and Cell Cultures using the Unlabeled Antibody Enzyme Technique

1976 ◽  
Vol 34 ◽  
pp. 266-267
Author(s):  
W. J. Hamilton
Keyword(s):  
Mammary Tumor ◽  
Leukemia Virus ◽  
Parallel Methods ◽  
Tumor Viruses ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
Antibody Conjugates ◽  
Rauscher Leukemia ◽  
Antigen Localization ◽  
Unlabeled Antibody

The study of RNA tumor viruses has been greatly facilitated by the use of immunochemical tagging methods. In the past these methods have been constrained to antibody conjugates with ferritin or peroxidase. In order to avoid the disadvantages of using conjugated antisera, investigators have applied the unlabeled antibody enzyme method of Sternberger to mammary tumor derived mouse cells prior to embedding for electron microscopy. The current study has successfully applied the Sternberger method to virusproducing cells and purified virus pellets after epoxy-embedding and ultrathin sectioning. The results demonstrate the distinct advantages of this “post-embedding” method for viral antigen localization.Purified Rauscher leukemia virus (RLV) and mouse mammary tumor virus (MMTV) were pelleted, fixed in buffered 2% paraformaldehyde and washed thoroughly. These were dehydrated in acetone, infiltrated and embedded in Spurr resin according to common procedures. A tumor derived cell line, Mm5mt, producing MMTV was embedded by parallel methods.

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