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Van Herreweghe F.,Unit for Molecular Signalling and Cell Death | Van Herreweghe F.,Ghent University | Festjens N.,Ghent University | Declercq W.,Unit for Molecular Signalling and Cell Death | And 3 more authors.
Cellular and Molecular Life Sciences | Year: 2010

In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor (TNF): cell survival through NF-κB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome. TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine-threonine kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology and pathogenesis of human diseases. © 2010 Springer Basel AG.

Wirawan E.,Unit for Molecular Signalling and Cell Death | Wirawan E.,Ghent University | Lippens S.,Unit for Molecular Signalling and Cell Death | Lippens S.,Ghent University | And 8 more authors.
Autophagy | Year: 2012

Beclin 1 (Atg6) is a well-known key regulator of autophagy. Although Beclin 1 is enzymatically inert, it governs the autophagic process by regulating PtdIns3KC3-dependent generation of phosphatidylinositol 3-phosphate (PtdIns(3)P) and the subsequent recruitment of additional Atg proteins that orchestrate autophagosome formation. Furthermore, Beclin 1 is implicated in numerous biological processes, including adaptation to stress, development, endocytosis, cytokinesis, immunity, tumorigenesis, aging and cell death. Whether all of these processes involve only the autophagy-inducing function of Beclin 1 is now being seriously questioned, because Beclin 1 appears to exercise several non-autophagy functions. Therefore, we should broaden our view of Beclin 1 as a specialized molecule in autophagy to that of a multifunctional protein. The central role of Beclin 1 in multiple signaling events obviously requires tight regulation at multiple levels. Its function is kept in check by diverse mechanisms, such as epigenetic silencing, microRNA regulation, post-translational modifications, and protein-protein interactions. Interestingly, multiple diseases are associated with deficiency or malfunction of Beclin 1, which makes it a potentially valuable target for various therapies, including anticancer treatment. In this review, we focus on Beclin 1 as a multifunctional protein, discuss the variety of mechanisms by which it is controlled, and give an overview of Beclin 1-associated pathologies. © 2012 Landes Bioscience.

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