Center for the Biology of Disease Leuven Belgium

Belgium

Center for the Biology of Disease Leuven Belgium

Belgium
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Salta E.,Center for the Biology of Disease Leuven Belgium | Sierksma A.,Center for the Biology of Disease Leuven Belgium | Vanden Eynden E.,Center for the Biology of Disease Leuven Belgium | De Strooper B.,Leuven University College
EMBO Molecular Medicine | Year: 2016

microRNA-132 (miR-132) is involved in prosurvival, anti-inflammatory and memory-promoting functions in the nervous system and has been found consistently downregulated in Alzheimer's disease (AD). Whether and how miR-132 deficiency impacts AD pathology remains, however, unaddressed. We show here that miR-132 loss exacerbates both amyloid and TAU pathology via inositol 1,4,5-trisphosphate 3-kinase B (ITPKB) upregulation in an AD mouse model. This leads to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation. We confirm downregulation of miR-132 and upregulation of ITPKB in three distinct human AD patient cohorts, indicating the pathological relevance of this pathway in AD. © 2016 EMBO.


Baietti M.F.,Center for the Biology of Disease Leuven Belgium | Simicek M.,Center for the Biology of Disease Leuven Belgium | Abbasi Asbagh L.,Center for the Biology of Disease Leuven Belgium | Radaelli E.,Center for the Biology of Disease Leuven Belgium | And 7 more authors.
EMBO Molecular Medicine | Year: 2016

Activation of the RAS oncogenic pathway, frequently ensuing from mutations in RAS genes, is a common event in human cancer. Recent reports demonstrate that reversible ubiquitination of RAS GTPases dramatically affects their activity, suggesting that enzymes involved in regulating RAS ubiquitination may contribute to malignant transformation. Here, we identified the de-ubiquitinase OTUB1 as a negative regulator of RAS mono- and di-ubiquitination. OTUB1 inhibits RAS ubiquitination independently of its catalytic activity resulting in sequestration of RAS on the plasma membrane. OTUB1 promotes RAS activation and tumorigenesis in wild-type RAS cells. An increase of OTUB1 expression is commonly observed in non-small-cell lung carcinomas harboring wild-type KRAS and is associated with increased levels of ERK1/2 phosphorylation, high Ki67 score, and poorer patient survival. Our results strongly indicate that dysregulation of RAS ubiquitination represents an alternative mechanism of RAS activation during lung cancer development. © 2016 EMBO.

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