Death receptor 4 (DR4) is a recently described receptor for the cytotoxic ligand TRAIL that reportedly uses a FADD-independent pathway to induce apoptosis and does not activate the NF-kappaB pathway. We have isolated a new member of the tumor necrosis factor receptor (TNFR) family, designated DR5, which bears a high degree of sequence homology to DR4. However, contrary to the previous reports, both DR4- and DR5-induced apoptosis can be blocked by dominant-negative FADD, and both receptors can activate NF-kappaB using a TRADD-dependent pathway. Finally, both receptors can interact with FADD, TRADD, and RIP. Thus, both DR5 and DR4 use FADD, TRADD, and RIP in their signal transduction pathways, and FADD is the common mediator of apoptosis by all known death domain-containing receptors.

No abstract

Merkel cell polyomavirus (MCV) is a recently discovered human virus closely related to African green monkey lymphotropic polyomavirus. MCV DNA is integrated in 80% of Merkel cell carcinomas (MCC), a neuroendocrine skin cancer linked to lymphoid malignancies such as chronic lymphocytic leukemia (CLL). To assess MCV infection and its association with human diseases, we developed a monoclonal antibody that specifically recognizes endogenous and transfected MCV large T (LT) antigen. We show expression of MCV LT protein localized to nuclei of tumor cells from MCC having PCR quantified MCV genome at an average of 5.2 (range 0.8-14.3) T antigen DNA copies per cell. Expression of this putative viral oncoprotein in tumor cells provides the mechanistic underpinning supporting the notion that MCV causes a subset of MCC. In contrast, although 2.2% of 325 hematolymphoid malignancies surveyed also showed evidence for MCV infection by DNA PCR, none were positive at high viral copy numbers, and none of 173 lymphoid malignancies examined on tissue microarrays expressed MCV LT protein in tumor cells. As with some of the other human polyomaviruses, lymphocytes may serve as a tissue reservoir for MCV infection, but hematolymphoid malignancies associated with MCC are unlikely to be caused by MCV. ' 2009 UICC

Death E ector Domains (DEDs) have been known to mediate the recruitment of Caspase 8 and its homologs to the aggregated death-inducing signaling complex (DISC), consisting of the death domain (DD)-containing receptors and various signaling proteins. In addition, several viruses were recently shown to encode proteins with DEDs (also called FLICE inhibitory proteins or vFLIPs) which have the ability of blocking cell death induced by DD-containing receptors. We provide evidence that vFLIPs can also modulate the NF-kB pathway and physically interact with several signaling proteins, such as the TRAFs, RIP, NIK and the IKKs. Modulation of the NF-kB pathway may play a role in the natural history of infection by these viruses.

No abstract

Caspase 8 is the most proximal caspase in the caspase cascade and has been known for its role in the mediation of cell death by various death receptors belonging to the TNFR family. We have discovered that Caspase 8 can activate the NF-kB pathway independent of its activity as a pro-apoptotic protease. This property is localized to its N-terminal prodomain, which contains two homologous death e ector domains (DEDs). Caspase 10 and MRIT, two DEDs-containing homologs of Caspase 8, can similarly activate the NF-kB pathway. Dominantnegative mutants of the Caspase 8 prodomain can block NF-kB induced by Caspase 8, FADD and several death receptors belonging to the TNFR family. Caspase 8 can interact with multiple proteins known to be involved in the activation of the NF-kB pathway, including the serine-threonine kinases RIP, NIK, IKK1 and IKK2. Thus, DEDs-containing caspases and caspase homolog(s) may have functions beyond their known role in the mediation of cell death. Oncogene (2000) 19, 4451 ± 4460.

Induction of MDR1 expression in response to cellular damage may account for increased MDR1 expression in treated human tumors. Protein kinase inhibitors may be useful in preventing the emergence of multidrug resistance during cancer chemotherapy.

Activation of the cascade of proteolytic caspases has been identified as the final common pathway of apoptosis in diverse biological systems. We have isolated a gene, termed MRIT, that possesses overall sequence homology to FLICE (MACH), a large prodomain caspase that links the aggregated complex of the death domain receptors of the tumor necrosis factor receptor family to downstream caspases. However, unlike FLICE, the C-terminal domain of MRIT lacks the caspase catalytic consensus sequence QAC(R͞Q)G. Nonetheless MRIT activates caspase-dependent death. Using yeast two-hybrid assays, we demonstrate that MRIT associates with caspases possessing large and small prodomains (FLICE, and CPP32͞YAMA), as well as with the adaptor molecule FADD. In addition, MRIT simultaneously and independently interacts with BclX L and FLICE in mammalian cells. Thus, MRIT is a mammalian protein that interacts simultaneously with both caspases and a Bcl-2 family member.