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A lot of fuss over Fas
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HEADLINES
A lot of fuss over Fas TAKAHASHI, T. et al. (1994) Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand Cell 76, 969-976 CHENG, J. et aL (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule Science 263, 1759-1762 Fas, a member of the tumour necrosis factor (TNF) receptor family, has recently been bathing in the limelight becauseof its role in mediating apoptosis. Interest in Fas was heightened by the report from Nagata and colleagues that mutations in the gene encoding Fas were responsible for the lymphoproliferative and autoimmune disorder in mice homozygous at the Ipr (lymphoproliferation) locus. This result indicated the importance of the Fas apoptosis-inducing system in the development and maintenance of a sound immune system, The cloning of the ligand for Fas from a cytotoxic T lymphocyte cell line showed it to be, not surprisingly, a member of the TNF family of mere. brahe.bound ligands. Now, Nagata and colleagues (Takahashi et aL)have confirmed speculation that the dis. order shown by gld mice (generalized
lymphoproliferati~e disease), which is similar but genetically distinct to that arising from defects at the Ipr locus, is the result of a point mutation in the Fas ligand. This mutation, which residesat the tip of the extracellular C-terminus of the Fas ligand, corresponds to a region of TNF-c~previously shown to affect the binding of TNF-cx to its cognate receptor, An unexpected turn of events was the characterization of a soluble Fas molecule by Mountz and colleagues (Cheng et aL). This molecule, which is thought to act as a suppressor of Fasmediated apoptosi~ by competing with membrane-bound Fasfor the Fas ligand, arises by alternative splicing, whereby the membrane-spanning region is deleted, The functional importance of soluble Fas is underlined by its presence in serum of normal donors and at
elevatedlevels in patients afflicted with autoimmune diseasessuch as systemic lupus erythematosus. Furthermore, treatment of mice with a genetically engineered soluble Fas molecule leads to perturbations of the immune response similar to those found in autoimmune disease. A soluble form of the Fas ligand has also been detected in cells transfected with gene constructs encoding the Fas ligand and in cytotoxic T cells that overexpressthe Fas ligand. Hence, a Yin-Yang relationship may exist between the two soluble members of this team, and imbalances may have severeconsequences: an excess of sol. uble Fas would allow the proliferation of those cells previously deemed to die via binding of the Fas ligand, whereas an abundance of soluble Fas ligand would be detrimental to those cells protected by the action of soluble Fas,
Oscillations In Ins(1,4,S)PJCa z÷ In tandem with the cell cycle CIAPA, B., PESANDO, D., WILDINC, M. and WHITAKER, M. (1994) Cell-cycle calcium transients driven by cyclic changes in inositol trisphosphate levels Nature 368, 875--878 Successive rounds of growth and division in eukaryotic cells are believed to be the result of periodic activation and inactivation of cyclin-dependent kinases (CDKs), driven in part by synthesis and destruction of cyclins, According to such models, the activity of each CDK towards its substrates (which may include other, down. stream kinases) leads to the cellular reorganization required for each phase of the cell cycle. This paper demonstrates the existence of an oscillating system with a role in the cell cycle that appears to be independent of the CDKs. 244
Whitaker's group show that the well-characterized Caz÷ transients of the sea urchin early embryonic cell cycles are driven by cyclic increases in inositol (1,4,5).trisphosphate [Ins(1,4,S)P3], hitherto considered a second messenger involved in transducing extracellular signals into cellularresponses.Theyshowthat Ins(1,4,S)P 3 peaks four times during the cell cycle, correlating with pronuclear migration, nuclear envelope breakdown, the metaphase--a~aphase transition and cytokinesis. Using heparin as an InsC1,4,S)P3antagorlist, they demonstrate that F Caz÷ peak is
required for mitotic entry. By inhibit. ing protein (and hence cyclin) synthesis, they also show that the Ins(1,4,5)P3 oscillations occur in the absenceof a CDK cycle. This work raises three important questions. What is the nature of the trigger that generates Ins(1,4,5)P 3 oscillations? How does Ins(1,4,S)P3/ Caa+ accomplish its role in the cell cycle? Finally, are the two cycles integrated, such that merely slowing down one cycle (rather than abolish. ing it, as the authors have done here) would affect the timing of the other7
TRENDS IN CELLBIOLOGYVOL. 4 JULY1994
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HEADLINES
A lot of fuss over Fas TAKAHASHI, T. et al. (1994) Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand Cell 76, 969-976 CHENG, J. et aL (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule Science 263, 1759-1762 Fas, a member of the tumour necrosis factor (TNF) receptor family, has recently been bathing in the limelight becauseof its role in mediating apoptosis. Interest in Fas was heightened by the report from Nagata and colleagues that mutations in the gene encoding Fas were responsible for the lymphoproliferative and autoimmune disorder in mice homozygous at the Ipr (lymphoproliferation) locus. This result indicated the importance of the Fas apoptosis-inducing system in the development and maintenance of a sound immune system, The cloning of the ligand for Fas from a cytotoxic T lymphocyte cell line showed it to be, not surprisingly, a member of the TNF family of mere. brahe.bound ligands. Now, Nagata and colleagues (Takahashi et aL)have confirmed speculation that the dis. order shown by gld mice (generalized
lymphoproliferati~e disease), which is similar but genetically distinct to that arising from defects at the Ipr locus, is the result of a point mutation in the Fas ligand. This mutation, which residesat the tip of the extracellular C-terminus of the Fas ligand, corresponds to a region of TNF-c~previously shown to affect the binding of TNF-cx to its cognate receptor, An unexpected turn of events was the characterization of a soluble Fas molecule by Mountz and colleagues (Cheng et aL). This molecule, which is thought to act as a suppressor of Fasmediated apoptosi~ by competing with membrane-bound Fasfor the Fas ligand, arises by alternative splicing, whereby the membrane-spanning region is deleted, The functional importance of soluble Fas is underlined by its presence in serum of normal donors and at
elevatedlevels in patients afflicted with autoimmune diseasessuch as systemic lupus erythematosus. Furthermore, treatment of mice with a genetically engineered soluble Fas molecule leads to perturbations of the immune response similar to those found in autoimmune disease. A soluble form of the Fas ligand has also been detected in cells transfected with gene constructs encoding the Fas ligand and in cytotoxic T cells that overexpressthe Fas ligand. Hence, a Yin-Yang relationship may exist between the two soluble members of this team, and imbalances may have severeconsequences: an excess of sol. uble Fas would allow the proliferation of those cells previously deemed to die via binding of the Fas ligand, whereas an abundance of soluble Fas ligand would be detrimental to those cells protected by the action of soluble Fas,
Oscillations In Ins(1,4,S)PJCa z÷ In tandem with the cell cycle CIAPA, B., PESANDO, D., WILDINC, M. and WHITAKER, M. (1994) Cell-cycle calcium transients driven by cyclic changes in inositol trisphosphate levels Nature 368, 875--878 Successive rounds of growth and division in eukaryotic cells are believed to be the result of periodic activation and inactivation of cyclin-dependent kinases (CDKs), driven in part by synthesis and destruction of cyclins, According to such models, the activity of each CDK towards its substrates (which may include other, down. stream kinases) leads to the cellular reorganization required for each phase of the cell cycle. This paper demonstrates the existence of an oscillating system with a role in the cell cycle that appears to be independent of the CDKs. 244
Whitaker's group show that the well-characterized Caz÷ transients of the sea urchin early embryonic cell cycles are driven by cyclic increases in inositol (1,4,5).trisphosphate [Ins(1,4,S)P3], hitherto considered a second messenger involved in transducing extracellular signals into cellularresponses.Theyshowthat Ins(1,4,S)P 3 peaks four times during the cell cycle, correlating with pronuclear migration, nuclear envelope breakdown, the metaphase--a~aphase transition and cytokinesis. Using heparin as an InsC1,4,S)P3antagorlist, they demonstrate that F Caz÷ peak is
required for mitotic entry. By inhibit. ing protein (and hence cyclin) synthesis, they also show that the Ins(1,4,5)P3 oscillations occur in the absenceof a CDK cycle. This work raises three important questions. What is the nature of the trigger that generates Ins(1,4,5)P 3 oscillations? How does Ins(1,4,S)P3/ Caa+ accomplish its role in the cell cycle? Finally, are the two cycles integrated, such that merely slowing down one cycle (rather than abolish. ing it, as the authors have done here) would affect the timing of the other7
TRENDS IN CELLBIOLOGYVOL. 4 JULY1994