Cell suicide gene cloned

Cell suicide gene cloned Researchers at the Massachusetts Institute of Technology (MIT) have cloned a suicide gene responsible for programmed cell death, or apoptosis, in the roundworm Caenorhabditis elegans, and, in a related study, scientists at Massachusetts General Hospital (MGH) demonstrated that a similar mammalian gene will cause programmed cell death in rat fibroblast cells. Junying Yuan, who worked with both research teams, said the findings should advance the understanding of the role of programmed cell death in embryonic development, tissue homoeostasis, inflammation, and disease. In the first paper, MIT researchers reported that they cloned ced-3, a gene essential for programmed cell death in C elegans. Then, by working with the sequences of the cloned cDNA, they deduced that the gene’s product is a 503 aminoacid protein whose active site is similar to that of interleukin-1-converting enzyme (ICE). ICE, a cysteine protease, cleaves the inactive precursor of IL-1 to generate the active cytokine. High levels of IL-L have been detected in Alzheimer’s disease, rheumatoid arthritis, septic shock, and head injury. The active site of the

ced-3 protein was also similar to the protein product of the mouse gene nedd-2, which is expressed during embryonic brain development and then down-regulated in the adult. In a follow-on study to the MIT lab’s work, researchers at MGH joined a promoter gene to the gene for murine ICE, introduced it into rat fibroblasts, and found that overexpression of ICE caused stereotypical programmed cell death in these mammalian cells. In addition, they found that the mammalian proto-oncogene bcl-2 and the viral gene crm-A could inhibit the cell death brought on by the overexpression of ICE gene. The researchers concluded, first, that the ced-3 protease acts to control programmed cell death in C elegans and, second, that members of the ced-3fICE/ nedd-2 gene family might function in programmed cell death in vertebrates. The inhibitory effect of bcl-2 suggests that not only does bcl-2 act to regulate cell death but also that the gene for ICE and other members of the ced-3fICE family could be recessive oncogenes, whose elimination could prevent normal cell death and pro-

Gene for Wilson’s disease Wilson’s disease (hepatolenticular degeneration) is an autosomal recessive disorder characterised by accumulation of copper in the liver and, when binding sites there are saturated, in the brain, cornea, and kidneys. The underlying biochemical abnormalities are reduced incorporation of copper into caeruloplasmin and defective biliary excretion of copper. The disorder can be treated effectively with penicillamine but is fatal if left untreated. Wilson’s disease is a classic example of an inborn error of metabolism. The gene that causes it has now been dissected.’-3 Linkage studies had already assigned the Wilson’s disease locus (WD) to chromosome 13ql4-3, and the impetus to define its position more precisely came partly from the recent isolation of the gene for Menkes’ disease (MNK), an X-linked disorder of copper metabolism. Although Wilson’s disease is primarily a defect of liver function, whereas the MNK gene is expressed in all tissues except the liver, the identification of the normal (wild-type)= MNK gene product as a copper-transporting P-type ATPase suggested that Wilson’s disease might also be caused by a defect in a copper transporter. Cox et al used a probe from the proposed copperbinding region of the MNK gene to search for a homologue on 13ql4-3. The result was the identification of a region some 30 kb long showing nearly 60% homology with AfA’7’C.’Tanzi et al used a different technique to isolate the WD gene and

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tthat one way an infecting virus may pro1long its host-cell’s life is by preventing its !suicide. "It is definitely to the advantage (of the virus to have the cell live longer", ,said Yuan. ICE, therefore, in addition 1 to eliciting immune response to viral i infection by activating IL-1, could also 1be initiating the suicide of infected cells, Yuan said, "so one stone kills two 1 birds". MIT researcher Shai Shaham said one focus of future research will be to identify sequences crucial to the function of ICE and related proteins. "Not only would this have implications for blocking or inactivating cell death in humans", Shaham said, "it could also be very useful in designing drugs that might interfere with ICE in its role in inflammation".

1 Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1-converting enzyme. Cell 1993; 75: 1-20. 2 Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J. Induction of apoptosis in fibroblasts by IL-1-converting enzyme, a mammalian homolog of the C elegans cell death gene ced-3. Cell 1993; 75: 653-60.

the viral gene crm-A inhibits ICE-induced cell death suggests

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MNK.3 Tanzi’s DNA analysis sequence revealed four disease-specific single-baseAgreement on the European Bioethics within mutations the WD three Convention, the first accord of its kind, pair gene, found in one or two affected should be clinched by the end of 1994, only being members among 115 families studied.3 two years later than originally envisaged, Tanzi et al predict difficulties with DNAsays the Council of Europe. Latest details were given at the Council’s second symbased genetic diagnosis because they expect more mutations to be found. For posium on bioethics in Strasbourg, Nov the present, screening of patients’ families 30-Dec 2. (This meeting coincided with will continue to be based on biochemical WHO call for international consultations tests. In the short term the most likely to secure a consensus on guidelines for benefit from isolating the WD and MNK research in genetics and biotechnology.) A genes will be a better understanding of pragmatic approach is being taken on a the molecular basis of copper homoeostatext that seeks to cover a subject in which sis. One question is why two structurally national divergence and technical progress similar genes have apparently paradoxical appear to be running ahead of the Straseffects: the MNK gene’s normal function bourg organisation’s efforts at harmonisation. The latest draft is a distillation of appears to be to ensure that dietary copis distributed to all tissues that need uncontroversial general principles such as it, per whereas the wild-type WD gene protects free and informed consent and adherence excessive accumulation. to professional standards. Many of these against copper are already the subject of non-binding Council of Europe recommendations. Dorothy Bonn 1 Bull

PC, Thomas GR, Rommens JM, Forbes

JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar 2

to

the Menkes gene. Nature Genet

1993; 5: 327-37. Petrukhin K, Fischer SG, Pirastu M, et al. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nature Genet 1993; 5:

338-43. 3 Tanzi RE, Petrukhin K, Chemov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes gene. Nature Genet 1993; 5: 345-50.

The specific issues of organ transplantation and medical research will be covered in separate protocols, although the latter text has yet to be agreed within the Convention’s main steering committee. Later, the Convention may be joined by a third specific protocol on the protection of the human embryo and fetus, but drafting has been postponed. In other areas, member states still differ. While unanimously agreeing that interventions on the human genome should have a therapeutic or diagnostic

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