RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases.
Animals
Arthritis
/ enzymology
Cell Death
Cell Line
Cell Line, Tumor
Colitis
/ etiology
Dermatitis
/ enzymology
Female
Gene Knock-In Techniques
Humans
Ileitis
/ etiology
Inflammation
/ enzymology
Intracellular Signaling Peptides and Proteins
/ genetics
Male
Melanoma, Experimental
/ pathology
Mice
Neoplasm Metastasis
Neoplasms
/ enzymology
Pancreatic Neoplasms
/ pathology
Protein Kinase Inhibitors
/ chemistry
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Rats
Receptor-Interacting Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
26
03
2019
accepted:
25
04
2019
revised:
19
04
2019
pubmed:
19
5
2019
medline:
7
4
2021
entrez:
19
5
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31101885
doi: 10.1038/s41418-019-0347-0
pii: 10.1038/s41418-019-0347-0
pmc: PMC7206119
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
NEMO protein, mouse
0
Protein Kinase Inhibitors
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
RIPK1 protein, human
EC 2.7.11.1
RIPK1 protein, rat
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk1 protein, mouse
EC 2.7.11.1
Ripk3 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
161-175Références
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