FADD/MORT1 Is a Common Mediator of CD95 (Fas/APO-1) and Tumor Necrosis Factor Receptor-induced Apoptosis

Chinnaiyan, Arul M.; Tepper, Clifford G.; Seldin, Michael F.; O’Rourke, Karen; Kischkel, Frank C.; Hellbardt, Stefan; Krammer, Peter H.; Peter, Marcus E.; Dixit, Vishva M.

doi:10.1074/jbc.271.9.4961

Cited by 684 publications

(90 citation statements)

References 33 publications

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“…In this study, the apoptotic response to Mith was accompanied by activation of a mitochondria-mediated apoptotic pathway through DR5/caspase-8 signaling. This phenomenon might also explain in part how Mith increases cell sensitivity to TNF-α31, as caspase-8 is implicated in TNF-mediated and death receptor-mediated apoptotic pathways40. Several regulators and effectors controlling the DR5-mediated apoptotic pathway might be involved in Mith-induced apoptosis.…”

Section: Discussionmentioning

confidence: 98%

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Choi

Nam

Jung

et al. 2014

Sci Rep

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Cervical cancer is the third most common cancer and the third leading cause of death among women. However, the standard treatment for cervical cancer includes cisplatin, which can cause side effects such as hematological damage or renal toxicity. New innovations in cervical cancer treatment focus on developing more effective and better-tolerated therapies such as Sp1-targeting drugs. Previous studies suggested that mithramycin A (Mith) inhibits the growth of various cancers by decreasing Sp1 protein. However, how Sp1 protein is decreased by Mith is not clear. Few studies have investigated the regulation of Sp1 protein by proteasome-dependent degradation as a possible control mechanism for the regulation of Sp1 in cancer cells. Here, we show that Mith decreased Sp1 protein by inducing proteasome-dependent degradation, thereby suppressing cervical cancer growth through a DR5/caspase-8/Bid signaling pathway. We found that prolonged Mith treatment was well tolerated after systemic administration to mice carrying cervical cancer cells. Reduction of body weight was minimal, indicating that Mith was a good therapeutic candidate for treatment of cancers in which Sp1 is involved in promoting and developing disease.

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Section: Discussionmentioning

confidence: 98%

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Choi

Nam

Jung

et al. 2014

Sci Rep

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“…Based on the existence of one of two distinct domains, the TNF-R superfamily members are divided into two subgroups, the death domain (DD)-containing receptors and TNF-R-associated factor (TRAF) interacting receptors [48]. The apoptotic cell death pathway is activated following recruitment of the Fas-associated death domain (FADD/MORT) protein to TRADD through interaction of the death domains (DD) [49]. FADD subsequently leads to activation of caspases and the release of pro-apoptotic factors from mitochondria to sustain the apoptotic signal [50] (Fig.…”

Section: Apoptosis Signaling Pathways In Hepatocytesmentioning

confidence: 99%

Diabetes and apoptosis: liver

Schattenberg

Schuchmann

2009

Apoptosis

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The liver is a central regulator of glucose homeostasis and stores or releases glucose according to metabolic demands. In insulin resistant states or diabetes the dysregulation of hepatic glucose release contributes significantly to the pathophysiology of these conditions. Acute or chronic liver disease can aggravate insulin resistance and the physiological effects of insulin on hepatocytes are disturbed. Insulin resistance has also been recognized as an independent risk factor for the development of liver injury. In the healthy liver tissue homeostasis is achieved through cell turnover by apoptosis and dysregulation of the physiological process resulting in too much or too little cell death can have potentially devastating effects on liver tissue. The delineation of the signaling pathways that mediate apoptosis changed the paradigms of understanding of many liver diseases. These signaling events include cell surface based receptor-ligand systems and intracellular signaling pathways that are regulated through kinases on multiple levels. The dissection of these signaling pathways has shown that the regulators of apoptosis signaling events in hepatocytes can also modulate insulin signaling pathways and that mediators of insulin resistance in turn influence liver cell apoptosis. This review will summarize the potential crosstalk between apoptosis and insulin resistance signaling events and discuss the involved mediators.

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“…These studies supported the hypothesis that DR signaling via Fas/FasL is crucial to the maintenance of lymphocyte homeostasis. It was thus surprising that mice lacking the function of FADD [59, 60], an essential signaling adaptor required for DR-induced apoptosis [61], failed to develop lymphoproliferative disease [62–64]. Subsequent investigation also revealed that loss of casp8, normally recruited to the death inducing signaling complex (DISC) via FADD following DR stimulation [10, 11, 60, 65], similarly failed to cause lymphoproliferative disease in humans and mice [15, 66].…”

Section: 4 T/b Cell Caspase 8 – Activation Pathwaymentioning

confidence: 99%

Functions of caspase 8: The identified and the mysterious

Salvesen¹,

Walsh²

2014

Seminars in Immunology

118

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Initially discovered as an initiator protease in apoptosis mediated by death receptors, caspase-8 is now known to have an apparently confounding opposing effect in securing cell survival. It is required to allow mouse embryo survival, and the survival of hematopoietic cells during their development and activation. Classic models in which caspase-8 is depleted or inhibited frequently result in inhibition of apoptosis, and conversion to death through a necrotic pathway. This bewildering switch is now known to be driven by activation of a pathway dependent on protein kinases of the RIP family, which engage a pathway known as necroptosis. If caspase-8 does not control this pathway, necrotic death results. The pro-apoptotic and pro-survival functions of caspase-8 are regulated by a specific interaction with the pseudo-caspase cFLIP, and it is thought that the heterocomplex between these two partners alters the substrate specificity of caspase-8 in favor of inactivating components of the RIP kinase pathway. The description of how caspase-8 and cFLIP coordinate the switch between apoptosis and survival is just beginning. The mechanism is not known, the differential targets are not known, and the reason of why an apoptotic initiator has been co-opted as a critical survival factor is only guessed at. Elucidating these unknowns will be important in understanding mechanisms and possible therapeutic targets in autoimmune, inflammatory, and metastatic diseases.

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FADD/MORT1 Is a Common Mediator of CD95 (Fas/APO-1) and Tumor Necrosis Factor Receptor-induced Apoptosis

Cited by 684 publications

References 33 publications

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Modulation of specificity protein 1 by mithramycin A as a novel therapeutic strategy for cervical cancer

Diabetes and apoptosis: liver

Functions of caspase 8: The identified and the mysterious

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