Tumour-necrosis factor (TNF) was discovered many years ago as a serum factor that was able to kill cancer cells in mice. The TNF receptor (TNFR) was shown to be expressed by mammalian cells years later, and led to the discovery of a superfamily of transmembrane proteins. These discoveries led to the identification of two gene families that include 18 ligands and 28 receptors, many of which are being targeted as anticancer therapies.
TNFR signalling was discovered to be an important aspect of the immune response, and family members such as FASL and APO2L/TRAIL induce apoptosis through a p53-independent mechanism. The signalling members of the TNFR superfamily can be divided into two main subgroups on the basis of their cytoplasmic region. One class of receptors, called death receptors (DR), contains a cytoplasmic death domain, whereas the other class does not.
APO2L/TRAIL has been shown to induce apoptosis in a wide variety of cancer cells, whereas most normal human cell types are resistant to APO2L/TRAIL-induced cell death.
Some TNFR family members do not signal, but act as 'decoys' that compete with receptors for ligands. A number of tumour types overexpress decoy receptors.
Treatment with factors that activate death-receptor signalling on cancer cells, and antibodies or small molecules that antagonize decoy receptors, might be an effective anticancer strategy.
Cancer cells often develop resistance to chemotherapy or irradiation through mutations in the p53 tumour-suppressor gene, which prevent apoptosis induction in response to cellular damage. Death receptors — members of the tumour-necrosis factor receptor (TNFR) superfamily — signal apoptosis independently of p53. Decoy receptors, by contrast, are a non-signalling subset of the TNFR superfamily that attenuate death-receptor function. Agents that are designed to activate death receptors (or block decoy receptors) might therefore be used to kill tumour cells that are resistant to conventional cancer therapies.
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<i>Saccharomyces</i> Genome Database
- FC DOMAIN
The antibody molecule can be proteolytically cleaved into two pieces — the F(ab′)2 fragment, which contains the antigen-binding activity, and the Fc domain, which carries out the effector function of the immunoglobin molecule.
- POLYHISTIDINE TAG
A type of epitope tag that is made up of six histidine residues (6X-His).
- EPITOPE TAG
A short amino-acid sequence that is added, in frame, to either end of a gene. This allows the recombinant protein to be easily detected and purified using antibodies against the tag. Commonly used tags include MYC, glutathione-S-transferase, and FLAG.
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Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2, 420–430 (2002). https://doi.org/10.1038/nrc821
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