International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

I30. NF-B RelA-Dependent Gene Products Mediating Anti-Apoptosis

Takahiro S. Doi1, Michael W. Marino1, Toshitada Takahashi2 Lloyd J. Old1, and Yuichi Obata2.
Ludwig Institute for Cancer Research at Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA,
Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681 Japan

Mice lacking RelA, a subunit of NF-B, die between days 14 and 15 of embryogenesis because of massive liver destruction. Embryonic fibroblasts isolated from RelA deficient embryos were found to be highly sensitive to TNF cytotoxicity, raising the possibility that RelA mediates an anti-apoptotic signal that protects normal cells from TNF cytotoxicity. To test this hypothesis, mutant mice lacking both RelA and TNF were derived. Embryogenesis proceeds normally in such mice, and TNF/RelA double-deficient mice are viable and have normal livers. Thus, RelA mediated anti-apoptotic signal that protects normal cells from TNF injury in vitro can be shown to be operative in vivo.

The search for TNF-mediated/NF-B RelA-dependent urvival genes is a major objective in this study. Several candidate urvival genes have been identified, but a comprehensive picture of TNF-mediated/NF-(B-dependent anti-apoptotic signaling has not yet emerged. Defining the nature of the NF-(B dependent anti-apoptotic signal and identifying its site of action in the apoptotic cascade initiated by TNF are critical to understanding why normal calls are usually resistant to the cytotoxic actions of TNF, and why this resistance is sometimes compromised in tumor cells. To identify proteins required for resistance to TNF cytotoxicity, subtractive hybridization was used to compare the cDNAs induced in TNF treated RelA+/+ cells relative to RelA-/- cells. Northern analysis was used to assess the induction of these cDNAs in TNF treated RelA+/+ and RelA-/- cells compared to untreated cells. This analysis has yielded a number of TNF inducible, RelA dependent cDNAs. Some of these cDNAs are novel, and are just starting to be characterized, while others are known and have been characterized by other groups. Some of the known genes, the gene for A20 or IAP for example, are thought to be important in resistance to apoptosis. Other known genes identified by our experiments, like those encoding the chemokines MIP, KC and JE, are not generally thought to be anti-apoptosis factors, although there is some evidence to suggest they may be important in this process. More likely, our collection of known and novel cDNAs represent a mix of cDNAs that are important both for the TNF induced, RelA mediated inflammatory response, and for resistance to TNF induced apoptosis. Transfection of these cDNAs into RelA deficient cells is the approach we are undertaking to determine whether these genes code for anti-apoptotic factors. In addition, the expression of these genes in a variety of TNF sensitive and resistant mouse and human tumor cell lines is being characterized to determine if their expression correlated with TNF sensitivity/ resistance.

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