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The chicken proto-oncogene c-rel encodes a transcription factor of the Rel/NF-κB family. We have previously shown that c-rel mRNAs accumulate in different types of apoptotic cells of the chick embryo, especially in mesenchymal cells within the four cell death areas of the limb bud: the anterior and posterior necrotic zones, the opaque patch and the interdigital necrotic zones. This study aimed to...
Tumor necrosis factor (TNF) is a pleiotropic cytokine that potentiates the cytotoxic effects of chemotherapeutic drugs. Although emergence of resistance to chemotherapeutic drugs is a major problem in cancer therapy, its mechanism is incompletely understood. Recently, activation of a nuclear transcription factor NF-κB has been reported to be a signal for anti-apoptosis. In this report, we investigated the effect of TNF on activation of NF-κB, c-Jun N-terminal kinase (JNK), and apoptosis in vincristine-resistant human histiocytic lymphoma U937-VR cells. Unlike the parent clone (U937-VS), no activation of caspase-3, known to be required for apoptosis, was found in vincristine-resistant cells on exposure to vincristine. These cells were also more resistant than U-937-VS cells to doxorubicin, daunomycin, and taxol. TNF-induced NF-κB activation, IκB α degradation, and nuclear translocation of p65 were all found to be highly suppressed in the U-937-VR cells. NF-κB activation by LPS, H...
Fractionated γ-irradiation (15 × 2 Gy in 3 weeks) induces a cellular resistance in HeLa cells against cisplatin exposure but not against irradiation. The mechanisms underlying this cellular resistance are associated with major changes in the TNFR1-dependent transduction pathway. The resistant HeLa/B cells exhibit increased levels of NF-κB with temporally independent regulation of the subunits NF-κB50...
Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development requires cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accetuated apoptosis, are now demonstrated as central defects in diverse human and murine autoimmune disease...
Prostate cancer progression and the development of androgen-independent prostate cancer have been largely related to a number of genetic abnormality that affect not only the androgen receptor but also crucial molecules involved in the regulation of survival or apoptotic pathways. One of these molecules, the pro-survival protein BCL-2, has been associated with the development of androgen-independent...
There are many factors contributing to the resistance to TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. However, it is not clear whether the mechanism of resistance to TRAIL is constitutive or inductive. Therefore, the purpose of this study was to investigate the resistant mechanisms to TRAIL at different levels in the apoptotic pathway. The human T-lymphoblastic...
TMS1/ASC is a bipartite protein comprising two protein-protein interaction domains, a pyrin domain (PYD) and a caspase recruitment domain (CARD). Proteins containing these domains play pivotal roles in regulating apoptosis and immune response pathways, and mutations in a number of PYD- and CARD-containing proteins have been linked to autoinflammatory diseases and cancer. Indeed, one of the ways in...
Inflammatory conditions are characterized by activation of the transcription factor nuclear factor kappa B (NF-κB), resulting in the expression of NF-κB-regulated, inflammation-related genes, such as inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). Expression of these genes contributes to the survival of cells. Indeed, exposure to pro-inflammatory cytokines in the absence of NF-κB...
Apoptosis is known to play a critical role in development and homeostasis in metazoans. Although apoptotic responses vary widely among cell types, the underlying mechanisms responsible for these differences are not known. In order to understand the molecular basis for these differences, we have studied a cell culture model comparing hepatoma cells to dedifferentiated cell lines derived from them....
These studies explore the molecular effect of arsenicals on MM cells. Freshly isolated cells derived from patients with advanced, chemo-refractory myeloma as well as human myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and to the inorganic compound AT. Both agents potently induced apoptosis in myeloma cells. Exposure to 1–5 μM AT or melarsoprol for...
Many members of tumor necrosis factor (TNF) superfamily are characterized by their ability to induce apoptosis once they bind in a homotrimeric manner to their cognate receptors. The receptor activator of nuclear factor-κB ligand (RANKL), a member of the TNF superfamily identified seven years ago, was originally described as a factor that induced osteoclastogenesis and dendritic cell survival. Recent...
At least three distinct chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) involving the API2 (also known as c-IAP2)-MALT1 fusion protein, BCL10, and MALT1, respectively, have been implicated in the molecular pathogenesis of mucosa associated lymphoid tissue (MALT) lymphoma. Our findings showed that several variants of the API2-MALT1 fusion protein can occur in patients...
The PI3-kinase/Akt pathway promotes cell survival in many different cell types including intestinal epithelial cells. Increased AKT activation in polyamine depleted intestinal epithelial cells correlated well with the decrease in TNF-α-induced apoptosis. Increased Akt activation and GSK3β (Ser 9) phosphorylation without significant effect on Bad (Ser136) phosphorylation indicate that Akt-mediated...
In the early 1990s it was discovered that the VP3/Apoptin protein encoded by the Chicken Anemia virus (CAV) possesses an inherent ability to specifically kill cancer cells. Apoptin was found to be located in the cytoplasm of normal cells while in tumor cells it was localized mainly in the nucleus.1 These differences in the localization pattern were suggested to be the main mechanism by which normal...
Chemosensitivity to anticancer drugs was compared between two human esophageal carcinoma cell lines, T.Tn and YES-6 cells. T.Tn cells were more resistant than YES-6 cells to peplomycin (PEP) but not to the other anticancer drugs such as camptothecin, mitomycin C and cytosine arabinoside. Western blot analysis showed higher expression levels of m-calpain and activated μ-calpain in T.Tn cells than in...
Nuclear factor κB (NF-κB) is a pleiotropic transcription factor implicated in the regulation of diverse morphologic cardiac alterations, for which the p50 and p65 subunits form the most prevalent dimeric form in the heart. NF-κB is inactivated by proteins of the IκB family, which trap it in the cytoplasm. It is not known whether NF-κB influences cardiac development. Objective: Here we investigated...
The identification of the most efficient strategy for tumor antigen loading of dendritic cells (DCs) remains a challenge in cancer immunotherapy protocols. Autologous dead tumor cells have been demonstrated to constitute an acceptable source of multiple tumor-associated antigens (TAA) to pulse DCs. However the optimal approach for inducing cell death that would lead to effective endocytosis and activation...
We have previously shown that UEV1 is up-regulated in all tumor cell lines examined and when SV40-transformed human embryonic kidney cells undergo immortalization; however, it is unclear whether and how UEV1 plays a critical role in this process. UEV1A encodes a ubiquitin conjugating enzyme variant, which is required for Ubc13 (ubiquitin conjugating enzyme) catalyzed poly-ubiquitination of target...
Spironolactone (SPIR) binds to cytoplasmic mineralocorticoid receptors (MR) and functions as an aldosterone (ALDO) antagonist. Recently, however, the drug was shown to have an early MR independent, suppressive effect on immunoactive and inflammatory cytokines as well as an apoptotic effect on blood mononuclear cells (MNC). To elucidate the mechanism behind SPIR’s apoptotic effect, we investigated...
Ajoene has been shown to induce apoptosis in 3T3-L1 adipocytes. In this report the effects on apoptosis of combinations of ajoene and trans-10, cis-12 conjugated linoleic acid (t10,c12CLA) in 3T3-L1 adipocytes were investigated. Although t10,c12CLA alone had no effect, ajoene plus t10,c12CLA reduced cell viability more than ajoene alone at 24 h (59.1 vs. 85.9% of control, respectively; p<0.05)...
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