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The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras.
- Source :
-
Molecular cell [Mol Cell] 2012 Mar 09; Vol. 45 (5), pp. 610-8. Date of Electronic Publication: 2012 Feb 08. - Publication Year :
- 2012
-
Abstract
- The connection between cancer and inflammation is widely recognized, yet the underlying molecular mechanisms are poorly understood. We report here that TIPE2 provides a molecular bridge from inflammation to cancer by targeting the Ras signaling pathway. TIPE2 binds the Ras-interacting domain of the RalGDS family of proteins, which are essential effectors of activated Ras. This binding prevented Ras from forming an active complex, thereby inhibiting the activation of the downstream signaling molecules Ral and AKT. Consequently, TIPE2 deficiency led to heightened activation of Ral and AKT, resistance to cell death, increased migration, and dysregulation of exocyst complex formation. Conversely, TIPE2 overexpression induced cell death and significantly inhibited Ras-induced tumorigenesis in mice. Importantly, TIPE2 expression was either completely lost or significantly downregulated in human hepatic cancer. Thus, TIPE2 is an inhibitor of both inflammation and cancer, and a potential drug target for inflammatory and neoplastic diseases.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Animals
Apoptosis genetics
Binding Sites
Binding, Competitive
Carcinoma, Hepatocellular genetics
Cell Movement genetics
Cell Transformation, Neoplastic genetics
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins metabolism
Liver Neoplasms genetics
Mice
Mice, Inbred C57BL
Middle Aged
NIH 3T3 Cells
Oncogene Protein v-akt genetics
ral GTP-Binding Proteins genetics
ral Guanine Nucleotide Exchange Factor metabolism
Genes, ras
Intracellular Signaling Peptides and Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 45
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 22326055
- Full Text :
- https://doi.org/10.1016/j.molcel.2012.01.006