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5. Grb7 knockout mice develop normally but litters born to knockout females fail to thrive.

Author

Lofgren, Kristopher A. and Kenny, Paraic A.

Subjects
KNOCKOUT mice, ADAPTOR proteins, ANIMAL weaning, PROTEIN-protein interactions, CELLULAR signal transduction
Abstract

Background: Growth factor receptor‐bound 7 (Grb7) is an adaptor protein involved in signal transduction downstream of multiple receptor tyrosine kinases, including ERBB, FGFR, and PDGFR pathways. Experimental studies have implicated Grb7 in regulating cell proliferation, survival, migration, and invasion through its large repertoire of protein–protein interactions. Results: Here, we describe the generation and characterization of a Grb7 knockout mouse. These mice are viable and fertile. A lacZ knock‐in reporter was used to visualize Grb7 promoter activity patterns in adult tissues, indicating widespread Grb7 expression in glandular epithelium, the central nervous system, and other tissues. The sole defect observed in these animals was a failure of Grb7 knockout females to successfully raise pups to weaning age, a phenotype that was independent of both paternal and pup genotypes. Conclusions: These data suggest a regulatory role for Grb7 in mammary lactational physiology. Key Findings: Despite many reports implicating Grb7 in multiple signal transduction pathways, deletion of this signaling adapter protein had minimal effects on mouse development.Grb7 knockout animals were viable and fertile but knockout females were deficient in the ability to raise pups to weaning age.These data imply a requirement for Grb7 in lactational sufficiency. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Identification of Wnt-1l0-catenin responsive genes in mouse mammary epithelial cells

Author

Kenny, Paraic A.

Subjects
616.99
Abstract

The Wnt/β-catenin signal transduction pathway plays a central role in metazoan development, controlling such diverse processes as cell growth, proliferation and organogenesis. Wnt-1 was initially identified as a mammary oncogene. Mutations in other components of this signal transduction pathway - APC, β-catenin and Axin - have been implicated in the initiation and progression of an increasing number of human malignancies. Aberrant activation of this pathway leads to the inappropriate expression of target genes such as c-MYC and CYCLIN D1. Elucidation of additional target genes of this pathway will shed further light upon the mechanisms underlying the malignant phenotype. As an in vitro model of Wnt/β-catenin signalling in the mouse mammary gland, mammary epithelial cell lines were generated in which this pathway could be activated in a tetracycline-dependent manner. The transcriptional consequences of aberrant Wnt/β-catenin signalling were then investigated using cDNA microarrays. Using this approach, 70 genes have been identified as being potential transcriptionally upregulated targets of the pathway and a similar number have been shown to be repressed. Similar experiments were performed in a colorectal cancer cell line lacking functional APC. An analysis of a representative sample of these differentially expressed genes is presented here. The use of human tumour tissue microarrays containing 300 tumour samples from a variety of tissues was validated as an approach to test the relevance of candidate genes.

Published
2002

18. Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells

Author

Kenny, Paraic A, Enver, Tariq, and Ashworth, Alan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Biotechnology, Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, Blotting, Northern, Blotting, Western, Cell Line, Cytoskeletal Proteins, Epithelial Cells, Extracellular Matrix Proteins, Green Fluorescent Proteins, Humans, Intercellular Signaling Peptides and Proteins, Intracellular Signaling Peptides and Proteins, Lipopolysaccharide Receptors, Mammary Glands, Animal, Membrane Proteins, Mice, Multienzyme Complexes, Neoplasms, Oligonucleotide Array Sequence Analysis, Phosphodiesterase I, Phosphoric Diester Hydrolases, Pyrophosphatases, Receptor Activity-Modifying Protein 3, Receptor Activity-Modifying Proteins, Recombinant Fusion Proteins, Trans-Activators, Transcription Factors, Up-Regulation, Wnt Proteins, Wnt1 Protein, beta Catenin, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Epidemiology
Abstract

BackgroundDeregulation of the Wnt/ beta-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in beta-catenin stabilization and accumulation, and the aberrant modulation of beta-catenin/TCF target genes. Such alterations in the cellular transcriptional profile are believed to underlie the pathogenesis of these cancers. We have sought to identify novel target genes of this pathway in mouse mammary epithelial cells.MethodsGene expression microarray analysis of mouse mammary epithelial cells inducibly expressing a constitutively active mutant of beta-catenin was used to identify target genes of this pathway.ResultsThe differential expression in response to DeltaNbeta-catenin for five putative target genes, Autotaxin, Extracellular Matrix Protein 1 (Ecm1), CD14, Hypoxia-inducible gene 2 (Hig2) and Receptor Activity Modifying Protein 3 (RAMP3), was independently validated by northern blotting. Each of these genes encodes either a receptor or a secreted protein, modulation of which may underlie the interactions between Wnt/beta-catenin tumour cells and between the tumour and its microenvironment. One of these genes, Hig2, previously shown to be induced by both hypoxia and glucose deprivation in human cervical carcinoma cells, was strongly repressed upon DeltaNbeta-catenin induction. The predicted N-terminus of Hig2 contains a putative signal peptide suggesting it might be secreted. Consistent with this, a Hig2-EGFP fusion protein was able to enter the secretory pathway and was detected in conditioned medium. Mutation of critical residues in the putative signal sequence abolished its secretion. The expression of human HIG2 was examined in a panel of human tumours and was found to be significantly downregulated in kidney tumours compared to normal adjacent tissue.ConclusionsHIG2 represents a novel non-cell autonomous target of the Wnt pathway which is potentially involved in human cancer.

Published
2005

21. Data from MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers

Author

Fricke, Stephanie L., primary, Payne, Susan N., primary, Favreau, Peter F., primary, Kratz, Jeremy D., primary, Pasch, Cheri A., primary, Foley, Tyler M., primary, Yueh, Alexander E., primary, Van De Hey, Dana R., primary, Depke, Mitchell G., primary, Korkos, Demetra P., primary, Sha, Gioia Chengcheng, primary, DeStefanis, Rebecca A., primary, Clipson, Linda, primary, Burkard, Mark E., primary, Lemmon, Kayla K., primary, Parsons, Benjamin M., primary, Kenny, Paraic A., primary, Matkowskyj, Kristina A., primary, Newton, Michael A., primary, Skala, Melissa C., primary, and Deming, Dustin A., primary

Published
2023
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22. Supplementary Table S1 from MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers

Author

Fricke, Stephanie L., primary, Payne, Susan N., primary, Favreau, Peter F., primary, Kratz, Jeremy D., primary, Pasch, Cheri A., primary, Foley, Tyler M., primary, Yueh, Alexander E., primary, Van De Hey, Dana R., primary, Depke, Mitchell G., primary, Korkos, Demetra P., primary, Sha, Gioia Chengcheng, primary, DeStefanis, Rebecca A., primary, Clipson, Linda, primary, Burkard, Mark E., primary, Lemmon, Kayla K., primary, Parsons, Benjamin M., primary, Kenny, Paraic A., primary, Matkowskyj, Kristina A., primary, Newton, Michael A., primary, Skala, Melissa C., primary, and Deming, Dustin A., primary

Published
2023
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26. Supplementary Figure S1 from MTORC1/2 Inhibition as a Therapeutic Strategy for PIK3CA Mutant Cancers

Author

Fricke, Stephanie L., primary, Payne, Susan N., primary, Favreau, Peter F., primary, Kratz, Jeremy D., primary, Pasch, Cheri A., primary, Foley, Tyler M., primary, Yueh, Alexander E., primary, Van De Hey, Dana R., primary, Depke, Mitchell G., primary, Korkos, Demetra P., primary, Sha, Gioia Chengcheng, primary, DeStefanis, Rebecca A., primary, Clipson, Linda, primary, Burkard, Mark E., primary, Lemmon, Kayla K., primary, Parsons, Benjamin M., primary, Kenny, Paraic A., primary, Matkowskyj, Kristina A., primary, Newton, Michael A., primary, Skala, Melissa C., primary, and Deming, Dustin A., primary

Published
2023
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27. Supplementary Table 1 from Relationship between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple-Negative Breast Cancer

Author

Sparano, Joseph A., primary, Goldstein, Lori J., primary, Childs, Barrett H., primary, Shak, Steven, primary, Brassard, Diana, primary, Badve, Sunil, primary, Baehner, Frederick L., primary, Bugarini, Roberto, primary, Rowley, Steve, primary, Perez, Edith A., primary, Shulman, Lawrence N., primary, Martino, Silvana, primary, Davidson, Nancy E., primary, Kenny, Paraic A., primary, Sledge, George W., primary, and Gray, Robert, primary

Published
2023
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28. Supplementary Figure 1 from Relationship between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple-Negative Breast Cancer

Author

Sparano, Joseph A., primary, Goldstein, Lori J., primary, Childs, Barrett H., primary, Shak, Steven, primary, Brassard, Diana, primary, Badve, Sunil, primary, Baehner, Frederick L., primary, Bugarini, Roberto, primary, Rowley, Steve, primary, Perez, Edith A., primary, Shulman, Lawrence N., primary, Martino, Silvana, primary, Davidson, Nancy E., primary, Kenny, Paraic A., primary, Sledge, George W., primary, and Gray, Robert, primary

Published
2023
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29. Supplementary Table 2 from Relationship between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple-Negative Breast Cancer

Author

Sparano, Joseph A., primary, Goldstein, Lori J., primary, Childs, Barrett H., primary, Shak, Steven, primary, Brassard, Diana, primary, Badve, Sunil, primary, Baehner, Frederick L., primary, Bugarini, Roberto, primary, Rowley, Steve, primary, Perez, Edith A., primary, Shulman, Lawrence N., primary, Martino, Silvana, primary, Davidson, Nancy E., primary, Kenny, Paraic A., primary, Sledge, George W., primary, and Gray, Robert, primary

Published
2023
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32. Supplementary Figure 2 from Relationship between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple-Negative Breast Cancer

Author

Sparano, Joseph A., primary, Goldstein, Lori J., primary, Childs, Barrett H., primary, Shak, Steven, primary, Brassard, Diana, primary, Badve, Sunil, primary, Baehner, Frederick L., primary, Bugarini, Roberto, primary, Rowley, Steve, primary, Perez, Edith A., primary, Shulman, Lawrence N., primary, Martino, Silvana, primary, Davidson, Nancy E., primary, Kenny, Paraic A., primary, Sledge, George W., primary, and Gray, Robert, primary

Published
2023
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33. Supplementary Table 3 from Relationship between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple-Negative Breast Cancer

Author

Sparano, Joseph A., primary, Goldstein, Lori J., primary, Childs, Barrett H., primary, Shak, Steven, primary, Brassard, Diana, primary, Badve, Sunil, primary, Baehner, Frederick L., primary, Bugarini, Roberto, primary, Rowley, Steve, primary, Perez, Edith A., primary, Shulman, Lawrence N., primary, Martino, Silvana, primary, Davidson, Nancy E., primary, Kenny, Paraic A., primary, Sledge, George W., primary, and Gray, Robert, primary

Published
2023
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42. miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling

Author

Bhagat, Tushar D., Zhou, Li, Sokol, Lubomir, Kessel, Rachel, Caceres, Gisela, Gundabolu, Krishna, Tamari, Roni, Gordon, Shanisha, Mantzaris, Ioannis, Jodlowski, Tomasz, Yu, Yiting, Jing, Xiaohong, Polineni, Rahul, Bhatia, Kavi, Pellagatti, Andrea, Boultwood, Jacqueline, Kambhampati, Suman, Steidl, Ulrich, Stein, Cy, Ju, Wenjun, Liu, Gang, Kenny, Paraic, List, Alan, Bitzer, Markus, and Verma, Amit

Published
2013
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