Natural Born Killer Research Articles

Chemists synthesize a natural-born killer

Neem-tree insecticide made in lab - but was it worth it?

Loss of the tissue-specific proapoptotic BH3-only protein Nbk/Bik is a unifying feature of renal cell carcinoma

We report for the first time inactivation of a tissue-specific Bcl-2 homology domain 3 (BH3)-only protein as a common aspect in human cancer. In detail, we show that loss of the BH3-only protein natural born killer (Nbk)/Bcl-2-interacting killer (Bik) is a common feature of clear-cell renal cell carcinoma (RCC). While strong Nbk expression is found in the renal tubuli and the epithelial lining of the glomerula, a consistent loss of Nbk expression was observed in primary RCC tissue and RCC cell lines. Mutation of Nbk is, however, rare, whereas deletion of the Nbk gene at 22q13.2 is frequent. In addition to loss of heterozygosity (LOH), DNA methylation mediates transcriptional silencing of the Nbk gene. The conditional restoration of Nbk/Bik expression led to apoptotic death of RCC but not of nonmalignant renal epithelia. A broader expression analysis of RCC cell lines for BH3-only proteins revealed that loss of Nbk coincides with failure to express Bim, whereas Puma, Bid and BNIP3 are readily detectable and, in case of Puma, inducible by p53. These data delineate a role for defects in BH3-only proteins as tumor suppressors in RCC and may explain at the same time the impressive clinical apoptosis resistance of RCC.

Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik

The proapoptotic BH3-only protein natural born killer / Bcl-2 interacting killer (Nbk/Bik) has been described to inhibit Bcl-2 and Bcl-xL, thereby supporting the death promoting ability of Bax. In order to evaluate its function in melanoma, we investigated the response after Nbk/Bik overexpression in cultured human melanoma cells and in a melanoma mouse model. Untransfected melanoma cell lines expressed Nbk/Bik only weakly at the mRNA and protein level. Conditional expression of Nbk/Bik by applying the inducible tetracycline-responsive expression system triggered apoptosis and enhanced sensitivity to proapoptotic stimuli as to agonistic CD95 activation and to chemotherapeutics etoposide, doxorubicin and pamidronate. For investigating the effects of Nbk/Bik in vivo, stably transfected melanoma cells were subcutaneously injected into nude mice. Significantly delayed tumor growth was the result when mice received doxycycline for induction of Nbk/Bik expression. By investigating the mechanism of Nbk/Bik-induced cell death, typical hallmarks of apoptosis such as DNA fragmentation and chromatin condensation were seen after induction. Interestingly, no indications for cytochrome c release and caspase processing were found, and selective caspase inhibition remained without effect. These data indicate the high potential of Nbk/Bik in regulating apoptosis in melanoma by a caspase-independent pathway and may corroborate the potency of novel antimelanoma strategies based on activation of BH3-only proteins such as Nbk/Bik.

Granzyme B: a natural born killer.

A main pathway used by cytotoxic T lymphocytes (CTLs) and natural killer cells to eliminate pathogenic cells is via exocytosis of granule components in the direction of the target cell, delivering a lethal hit of cytolytic molecules. Amongst these, granzyme B and perforin have been shown to induce CTL-mediated target cell DNA fragmentation and apoptosis. Once released from the CTL, granzyme B binds its receptor, the mannose-6-phosphate/insulin-like growth factor II receptor, and is endocytosed but remains arrested in endocytic vesicles until released by perforin. Once in the cytosol, granzyme B targets caspase-3 directly or indirectly through the mitochondria, initiating the caspase cascade to DNA fragmentation and apoptosis. Caspase activity is required for apoptosis to occur; however, in the absence of caspase activity, granzyme B can still initiate mitochondrial events via the cleavage of Bid. Recent work shows that granzyme B-mediated release of apoptotic factors from the mitochondria is essential for the full activation of caspase-3. Thus, granzyme B acts at multiple points to initiate the death of the offending cell. Studies of the granzyme B death receptor and internal signaling pathways may lead to critical advances in cell transplantation and cancer therapy.

Natural born killer: tau protein and its role in dementia

Tau is a candidate gene for chromosome 17 fron‐totemporal dementia Poorkaj et al. (1998) Ann Neurol 43: 815–825Association of missense and 5′‐splice‐site mutations in tau with the inherited dementia FTDP‐17 Hutton et al. (1998) Nature 393: 702–705Mutation in the tau gene in familial multiple system tauopathy with presenile dementia Spillantini et al. (1998) Proc Natl Acad Sci USA 95: 7737–7741

The Last Post:Henry V, War Culture and the Postmodern Shakespeare

“Marketing, that mysterious part of the theatre industry, can produce surprising effects,” observes Peter Holland in his recent book on Shakespearean production in Britain during the 1990s. Discussing the material constraints on the repertory of the Royal Shakespeare Company, Holland cites the promotion of the 1994 production ofCoriolanusas it transferred to the Barbican, which, knowingly addressed a “youth” market versed in the work of Oliver Stone and Quentin Tarantino. The RSC poster displayed a blood-soaked Toby Stephens in the title role, accompanied by the slogan “A natural born killer too.” For an even more surprising and mysterious example of optimistically modish marketing, consider the tactics of the newspaper advertisement announcing the 1996 season at Stratford-upon-Avon. Avoiding any direct mention of Shakespeare, his plays, or theatre, it pictured an ominously darkened cloudscape, with slogans projected onto it, almost like skywriting. These posed a question, “Virtual reality?” and a riposte: “Try the real thing.”