Impaired regulation of NF-κB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice

Zhang, Jun; Stirling, Brigid; Temmerman, Stéphane; Chi, Aiping; Fuss, Ivan J.; Derry, Jonathan M.J.; Jain, Ashish

doi:10.1172/jci28746

Cited by 231 publications

(255 citation statements)

References 31 publications

(41 reference statements)

Supporting

Mentioning

241

Contrasting

Unclassified

Order By: Relevance

“…52,85 The association of CYLD with TNFR1 signaling was first made when CYLD was shown to disassemble K63-linked chains from NEMO and TRAF proteins to attenuate downstream signaling cascades. 33,86,87 These data have been supported by studies in CYLD À/À cells and animals, 88,89 and similar mechanisms appear to be conserved in Drosophila. 90 However, the role of CYLD in TNF-a-induced RIP1 de-ubiquitination is less clear.…”

Section: Dr Signaling Is Regulated By Ubiquitinationmentioning

confidence: 61%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

111

View full text Add to dashboard Cite

The study of death receptor (DR) signaling has led to the discovery of new signaling paradigms, including the first example of direct receptor-mediated activation of a protease (caspase-8) that functions as a second messenger to initiate a 'death cascade' of downstream protease activation. More recently, this receptor system has underscored the importance of ubiquitin modification in NF-jB activation. Both degradative lysine 48-linked polyubiquitin and scaffolding lysine 63-linked polyubiquitin have an essential role in signal propagation. Remarkably, a negative feedback process, termed ubiquitin editing, regulates signaling that emanates from certain DRs. Ubiquitin editing is mediated by a complex interplay between the ubiquitination and deubiquitination machinery, resulting in the replacement of signal enhancing lysine 63-linked polyubiquitin with signal extinguishing lysine 48-linked polyubiquitin. The ubiquitination machinery and its regulation in the context of DR signaling are discussed herein. The tumor necrosis factor receptor (TNFR) family is characterized by the presence of a variable number of cysteinerich domains within the extracellular segment and includes receptors known as the death receptors (DRs). The cognate ligands function in concert with the receptors to orchestrate immune responses, generate secondary lymphoid organs, and modulate the survival, proliferation, and differentiation of responding cells. When this axis goes awry, it can contribute to sepsis, cachexia, and autoimmune disorders including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. 1,2 Indeed, therapeutics based on neutralization of tumor necrosis factor-a (TNF-a) have met unparalleled success in the treatment of many autoimmune disorders. Furthermore, there has been a recent groundswell of enthusiasm for exploiting the proapoptotic properties of the DRs for TRAIL/ Apo2 ligand that selectively mediate the demise of tumor cells.There are six TNFR family DRs identified in humans to date: Fas/CD-95, TNFR1, DR3, DR4, DR5, and DR6. They are characterized by the presence of an B80-residue motif within their cytosolic segments dubbed the death domain (DD). 1,2 The integrity of this domain is essential for engaging downstream signaling components that, depending on the cellular context, promote either prosurvival and proinflammatory signaling pathways or promote apoptosis. 1,2 The DD is sixhelical fold that adopts a 'Greek key' topology and mediates homotypic interactions. There are four death-fold motifs: the DD itself, the death effector domain (DED), caspase activation and recruitment domain (CARD), and the Pyrin domain. 3 Although these folds all possess a similar topological configuration, their surface charge is distinct such that specificity of association is dictated by electrostatic interactions. 3 The DRs initiate signaling by recruiting one of two DD-containing platform adaptor molecules: FADD (Fas Associated Death Domain) that generally mediates apoptosis and/or TRADD (TNF Receptor Associated Death Domain)...

show abstract

Section: Dr Signaling Is Regulated By Ubiquitinationmentioning

confidence: 61%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

111

View full text Add to dashboard Cite

show abstract

“…Mice lacking CYLD show increased sensitivity to dextran sodium sulfate (DSS)-induced colitis, presumably due to an exacerbated response of CYLDdeficient immune cells to the destruction of the epithelial barrier by the DSS treatment [24]. Similarly, mice lacking single immunoglobulin IL-1R-related (SIGIRR) develop more severe colon inflammation after DSS treatment [25][26][27].…”

Section: Detrimental Role For Nf-κb Activation In the Intestinementioning

confidence: 99%

NF-κB in the regulation of epithelial homeostasis and inflammation

2010

View full text Add to dashboard Cite

The IκB kinase/NF-κB signaling pathway has been implicated in the pathogenesis of several inflammatory diseases. Increased activation of NF-κB is often detected in both immune and non-immune cells in tissues affected by chronic inflammation, where it is believed to exert detrimental functions by inducing the expression of proinflammatory mediators that orchestrate and sustain the inflammatory response and cause tissue damage. Thus, increased NF-κB activation is considered an important pathogenic factor in many acute and chronic inflammatory disorders, raising hopes that NF-κB inhibitors could be effective for the treatment of inflammatory diseases. However, ample evidence has accumulated that NF-κB inhibition can also be harmful for the organism, and in some cases trigger the development of inflammation and disease. These findings suggested that NF-κB signaling has important functions for the maintenance of physiological immune homeostasis and for the prevention of inflammatory diseases in many tissues. This beneficial function of NF-κB has been predominantly observed in epithelial cells, indicating that NF-κB signaling has a particularly important role for the maintenance of immune homeostasis in epithelial tissues. It seems therefore that NF-κB displays two faces in chronic inflammation: on the one hand increased and sustained NF-κB activation induces inflammation and tissue damage, but on the other hand inhibition of NF-κB signaling can also disturb immune homeostasis, triggering inflammation and disease. Here, we discuss the mechanisms that control these apparently opposing functions of NF-κB signaling, focusing particularly on the role of NF-κB in the regulation of immune homeostasis and inflammation in the intestine and the skin.

show abstract

“…The generation of mutant mice deficient in CYLD has confirmed the tumor-suppressor role of this DUB because of its ability to enhance NK-kB activity (Zhang et al, 2006b). In the case of A20, chromosomal deletions and inactivating mutations have been found in several lymphoma subtypes (Honma et al, 2009;Novak et al, 2009), whereas point mutations and deletions in BAP1 have been described in breast and lung cancer (Jensen et al, 1998;Harbour et al, 2010).…”

Section: Genetic or Functional Alterations Of Dubs In Cancermentioning

confidence: 93%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

View full text Add to dashboard Cite

Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

show abstract

Impaired regulation of NF-κB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice

Cited by 231 publications

References 31 publications

Regulation of death receptor signaling by the ubiquitin system

Regulation of death receptor signaling by the ubiquitin system

NF-κB in the regulation of epithelial homeostasis and inflammation

Deubiquitinases in cancer: new functions and therapeutic options

Contact Info

Product

Resources

About