| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T45758 | ||||
| Target Name | Tumor necrosisfactor receptor superfamily member 5 | ||||
| Target Type | Clinical Trial |
||||
| Action against Disease Model | Dacetuzumab | Dacetuz uMab activates two distinct proapoptotic signaling pathways, overcoming transformation events key to the pathogenesis of NHL. Dacetuz uMab-mediated CD40 signaling constitutively activated the nuclear factor-|?B and mitogen-activated protein kinase signaling pathways producing the sustained downregulation of B-cell lymphoma 6 (BCL-6), an oncoprotein implicated in lymphomagenesis. Loss of BCL-6 resulted in c-Myc downregulation and activation of a transcriptional program characteristic of early B-cell maturation, concomitant with reduced proliferation and cell death. | [553094] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Soluble CD40 ligand(sCD40L) strongly enhances platelet activation and aggregation. H uMan platelets treated with a mutated form of sCD40L that does not bind CD40, and CD40(-/-) mouse platelets failed to elicit such responses. Furthermore, sCD40L stimulation induces the association of the t uMor necrosis factor receptor-associated factor-2 with platelet CD40. Notably, sCD40L primes platelets through activation of the small GTPase Rac1 and its downstream target p38 mitogen-activated protein kinase, which leads to platelet shape change and actin polymerization. Moreover, sCD40L exacerbates thrombus formation and leukocyte infiltration in wild-type mice but not in CD40(-/-) mice.sCD40L enhances agonist-induced platelet activation and aggregation through a CD40-dependent t uMor necrosis factor receptor-associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway. Thus, sCD40L is an important platelet primer predisposing platelets to enhanced thrombus formation in response to vascular injury. This may explain the link between circulating levels of sCD40L and cardiovascular diseases. | [553094] | |||
| References | |||||
| Ref 553094 | Proapoptotic signaling activity of the anti-CD40 monoclonal antibody dacetuzumab circumvents multiple oncogenic transformation events and chemosensitizes NHL cells. Leukemia. 2011 Jun;25(6):1007-16. doi: 10.1038/leu.2011.21. Epub 2011 Mar 11. | ||||
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