RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases
| Autor: | Patrick Caplazi, P. Bir Kohli, Joshua D. Webster, M. van Lookeren Campagne, Allie Maltzman, Gregory Hamilton, Wyne P. Lee, Evgeny Varfolomeev, Rina Fong, Brent S. McKenzie, Melissa R. Junttila, Swathi Sujatha-Bhaskar, Juan Zhang, Katherine E. Wickliffe, Patrick J. Lupardus, Debra L. Dugger, Domagoj Vucic, Snahel Patel, J.H. Cheng, Bianca M. Liederer, Kim Newton, Youngsu Kwon, Sreemathy Ramaswamy, Adam R. Johnson, Gauri Deshmukh |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Programmed cell death Necroptosis Melanoma Experimental Dermatitis Inflammation Protein Serine-Threonine Kinases Article Cell Line Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Neoplasms Cell death and immune response medicine Animals Humans Gene Knock-In Techniques Neoplasm Metastasis Kinase activity Acute inflammation Protein Kinase Inhibitors Molecular Biology Cell Death Kinase business.industry Arthritis Melanoma Intracellular Signaling Peptides and Proteins Cell Biology Ileitis Colitis medicine.disease Rats Pancreatic Neoplasms 030104 developmental biology Tumor progression Receptor-Interacting Protein Serine-Threonine Kinases 030220 oncology & carcinogenesis Cancer research Female medicine.symptom Signal transduction business |
| Zdroj: | Cell Death and Differentiation |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/s41418-019-0347-0 |
| Popis: | The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting RIP1 genetically, using knock-in mice that express catalytically inactive RIP1 D138N, or pharmacologically, using the murine-potent inhibitor GNE684. Inhibition of RIP1 reduced collagen antibody-induced arthritis, and prevented skin inflammation caused by mutation of Sharpin, or colitis caused by deletion of Nemo from intestinal epithelial cells. Conversely, inhibition of RIP1 had no effect on tumor growth or survival in pancreatic tumor models driven by mutant Kras, nor did it reduce lung metastases in a B16 melanoma model. Collectively, our data emphasize a role for the kinase activity of RIP1 in certain inflammatory disease models, but question its relevance to tumor progression and metastases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink