Abstract
Vitamin A and its derivatives, the retinoids, are essential regulators of many important biological functions, including cell growth and differentiation, development, homeostasis, and carcinogenesis. Natural retinoids such as all-trans retinoic acid can induce cell differentiation and inhibit growth of certain cancer cells. We recently identified a novel class of synthetic retinoids with strong anti-cancer cell activities in vitro and in vivo which can induce apoptosis in several cancer cell lines. Using an electrophoretic mobility shift assay, we analyzed the DNA binding activity of several transcription factors in T cells treated with apoptotic retinoids. We found that the DNA binding activity of the general transcription factor Sp1 is lost in retinoid-treated T cells undergoing apoptosis. A truncated Sp1 protein is detected by immunoblot analysis, and cytosolic protein extracts prepared from apoptotic cells contain a protease activity which specifically cleaves purified Sp1 in vitro. This proteolysis of Sp1 can be inhibited by N-ethylmaleimide and iodoacetamide, indicating that a cysteine protease mediates cleavage of Sp1. Furthermore, inhibition of Sp1 cleavage by ZVAD-fmk and ZDEVD-fmk suggests that caspases are directly involved in this event. In fact, caspases 2 and 3 are activated in T cells after treatment with apoptotic retinoids. The peptide inhibitors also blocked retinoid-induced apoptosis, as well as processing of caspases and proteolysis of Sp1 and poly(ADP-ribose) polymerase in intact cells. Degradation of Sp1 occurs early during apoptosis and is therefore likely to have profound effects on the basal transcription status of the cell. Interestingly, retinoid-induced apoptosis does not require de novo mRNA and protein synthesis, suggesting that a novel mechanism of retinoid signaling is involved, triggering cell death in a transcriptional activation-independent, caspase-dependent manner.
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- Alnemri E. S., Livingston D. J., Nicholson D. W., Salvesen G., Thornberry N. A., Wong W. W., Yuan J. Human ICE/CED-3 protease nomenclature. Cell. 1996 Oct 18;87(2):171–171. doi: 10.1016/s0092-8674(00)81334-3. [DOI] [PubMed] [Google Scholar]
- Armstrong R. C., Aja T., Xiang J., Gaur S., Krebs J. F., Hoang K., Bai X., Korsmeyer S. J., Karanewsky D. S., Fritz L. C. Fas-induced activation of the cell death-related protease CPP32 Is inhibited by Bcl-2 and by ICE family protease inhibitors. J Biol Chem. 1996 Jul 12;271(28):16850–16855. doi: 10.1074/jbc.271.28.16850. [DOI] [PubMed] [Google Scholar]
- Bernard B. A., Bernardon J. M., Delescluse C., Martin B., Lenoir M. C., Maignan J., Charpentier B., Pilgrim W. R., Reichert U., Shroot B. Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor gamma. Biochem Biophys Res Commun. 1992 Jul 31;186(2):977–983. doi: 10.1016/0006-291x(92)90842-9. [DOI] [PubMed] [Google Scholar]
- Block K. L., Shou Y., Poncz M. An Ets/Sp1 interaction in the 5'-flanking region of the megakaryocyte-specific alpha IIb gene appears to stabilize Sp1 binding and is essential for expression of this TATA-less gene. Blood. 1996 Sep 15;88(6):2071–2080. [PubMed] [Google Scholar]
- Boldin M. P., Goncharov T. M., Goltsev Y. V., Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803–815. doi: 10.1016/s0092-8674(00)81265-9. [DOI] [PubMed] [Google Scholar]
- Boldin M. P., Varfolomeev E. E., Pancer Z., Mett I. L., Camonis J. H., Wallach D. A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem. 1995 Apr 7;270(14):7795–7798. doi: 10.1074/jbc.270.14.7795. [DOI] [PubMed] [Google Scholar]
- Brancolini C., Benedetti M., Schneider C. Microfilament reorganization during apoptosis: the role of Gas2, a possible substrate for ICE-like proteases. EMBO J. 1995 Nov 1;14(21):5179–5190. doi: 10.1002/j.1460-2075.1995.tb00202.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bump N. J., Hackett M., Hugunin M., Seshagiri S., Brady K., Chen P., Ferenz C., Franklin S., Ghayur T., Li P. Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35. Science. 1995 Sep 29;269(5232):1885–1888. doi: 10.1126/science.7569933. [DOI] [PubMed] [Google Scholar]
- Casciola-Rosen L. A., Miller D. K., Anhalt G. J., Rosen A. Specific cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death. J Biol Chem. 1994 Dec 9;269(49):30757–30760. [PubMed] [Google Scholar]
- Chinnaiyan A. M., O'Rourke K., Lane B. R., Dixit V. M. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science. 1997 Feb 21;275(5303):1122–1126. doi: 10.1126/science.275.5303.1122. [DOI] [PubMed] [Google Scholar]
- Chinnaiyan A. M., O'Rourke K., Tewari M., Dixit V. M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995 May 19;81(4):505–512. doi: 10.1016/0092-8674(95)90071-3. [DOI] [PubMed] [Google Scholar]
- Delia D., Aiello A., Formelli F., Fontanella E., Costa A., Miyashita T., Reed J. C., Pierotti M. A. Regulation of apoptosis induced by the retinoid N-(4-hydroxyphenyl) retinamide and effect of deregulated bcl-2. Blood. 1995 Jan 15;85(2):359–367. [PubMed] [Google Scholar]
- Delia D., Aiello A., Lombardi L., Pelicci P. G., Grignani F., Grignani F., Formelli F., Menard S., Costa A., Veronesi U. N-(4-hydroxyphenyl)retinamide induces apoptosis of malignant hemopoietic cell lines including those unresponsive to retinoic acid. Cancer Res. 1993 Dec 15;53(24):6036–6041. [PubMed] [Google Scholar]
- Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ellis R. E., Yuan J. Y., Horvitz H. R. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. doi: 10.1146/annurev.cb.07.110191.003311. [DOI] [PubMed] [Google Scholar]
- Emoto Y., Manome Y., Meinhardt G., Kisaki H., Kharbanda S., Robertson M., Ghayur T., Wong W. W., Kamen R., Weichselbaum R. Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells. EMBO J. 1995 Dec 15;14(24):6148–6156. doi: 10.1002/j.1460-2075.1995.tb00305.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Enari M., Talanian R. V., Wong W. W., Nagata S. Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis. Nature. 1996 Apr 25;380(6576):723–726. doi: 10.1038/380723a0. [DOI] [PubMed] [Google Scholar]
- Fanjul A. N., Delia D., Pierotti M. A., Rideout D., Yu J. Q., Pfahl M., Qiu J. 4-Hydroxyphenyl retinamide is a highly selective activator of retinoid receptors. J Biol Chem. 1996 Sep 13;271(37):22441–22446. doi: 10.1074/jbc.271.37.22441. [DOI] [PubMed] [Google Scholar]
- Faucheu C., Diu A., Chan A. W., Blanchet A. M., Miossec C., Hervé F., Collard-Dutilleul V., Gu Y., Aldape R. A., Lippke J. A. A novel human protease similar to the interleukin-1 beta converting enzyme induces apoptosis in transfected cells. EMBO J. 1995 May 1;14(9):1914–1922. doi: 10.1002/j.1460-2075.1995.tb07183.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fernandes-Alnemri T., Litwack G., Alnemri E. S. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme. J Biol Chem. 1994 Dec 9;269(49):30761–30764. [PubMed] [Google Scholar]
- Fernandes-Alnemri T., Litwack G., Alnemri E. S. Mch2, a new member of the apoptotic Ced-3/Ice cysteine protease gene family. Cancer Res. 1995 Jul 1;55(13):2737–2742. [PubMed] [Google Scholar]
- Gu Y., Sarnecki C., Aldape R. A., Livingston D. J., Su M. S. Cleavage of poly(ADP-ribose) polymerase by interleukin-1 beta converting enzyme and its homologs TX and Nedd-2. J Biol Chem. 1995 Aug 11;270(32):18715–18718. doi: 10.1074/jbc.270.32.18715. [DOI] [PubMed] [Google Scholar]
- Gégonne A., Bosselut R., Bailly R. A., Ghysdael J. Synergistic activation of the HTLV1 LTR Ets-responsive region by transcription factors Ets1 and Sp1. EMBO J. 1993 Mar;12(3):1169–1178. doi: 10.1002/j.1460-2075.1993.tb05758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henkart P. A. ICE family proteases: mediators of all apoptotic cell death? Immunity. 1996 Mar;4(3):195–201. doi: 10.1016/s1074-7613(00)80428-8. [DOI] [PubMed] [Google Scholar]
- Howard A. D., Kostura M. J., Thornberry N., Ding G. J., Limjuco G., Weidner J., Salley J. P., Hogquist K. A., Chaplin D. D., Mumford R. A. IL-1-converting enzyme requires aspartic acid residues for processing of the IL-1 beta precursor at two distinct sites and does not cleave 31-kDa IL-1 alpha. J Immunol. 1991 Nov 1;147(9):2964–2969. [PubMed] [Google Scholar]
- Hsu H., Xiong J., Goeddel D. V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995 May 19;81(4):495–504. doi: 10.1016/0092-8674(95)90070-5. [DOI] [PubMed] [Google Scholar]
- Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
- Jones K. A., Kadonaga J. T., Luciw P. A., Tjian R. Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1. Science. 1986 May 9;232(4751):755–759. doi: 10.1126/science.3008338. [DOI] [PubMed] [Google Scholar]
- Jänicke R. U., Walker P. A., Lin X. Y., Porter A. G. Specific cleavage of the retinoblastoma protein by an ICE-like protease in apoptosis. EMBO J. 1996 Dec 16;15(24):6969–6978. [PMC free article] [PubMed] [Google Scholar]
- Karlseder J., Rotheneder H., Wintersberger E. Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F. Mol Cell Biol. 1996 Apr;16(4):1659–1667. doi: 10.1128/mcb.16.4.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kaufmann S. H., Desnoyers S., Ottaviano Y., Davidson N. E., Poirier G. G. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 1993 Sep 1;53(17):3976–3985. [PubMed] [Google Scholar]
- Kostura M. J., Tocci M. J., Limjuco G., Chin J., Cameron P., Hillman A. G., Chartrain N. A., Schmidt J. A. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5227–5231. doi: 10.1073/pnas.86.14.5227. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kumar S. ICE-like proteases in apoptosis. Trends Biochem Sci. 1995 May;20(5):198–202. doi: 10.1016/s0968-0004(00)89007-6. [DOI] [PubMed] [Google Scholar]
- Kumar S., Kinoshita M., Noda M., Copeland N. G., Jenkins N. A. Induction of apoptosis by the mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1 beta-converting enzyme. Genes Dev. 1994 Jul 15;8(14):1613–1626. doi: 10.1101/gad.8.14.1613. [DOI] [PubMed] [Google Scholar]
- Lazebnik Y. A., Kaufmann S. H., Desnoyers S., Poirier G. G., Earnshaw W. C. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994 Sep 22;371(6495):346–347. doi: 10.1038/371346a0. [DOI] [PubMed] [Google Scholar]
- Lazebnik Y. A., Takahashi A., Moir R. D., Goldman R. D., Poirier G. G., Kaufmann S. H., Earnshaw W. C. Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9042–9046. doi: 10.1073/pnas.92.20.9042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lin S. Y., Black A. R., Kostic D., Pajovic S., Hoover C. N., Azizkhan J. C. Cell cycle-regulated association of E2F1 and Sp1 is related to their functional interaction. Mol Cell Biol. 1996 Apr;16(4):1668–1675. doi: 10.1128/mcb.16.4.1668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu X., Zou H., Slaughter C., Wang X. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997 Apr 18;89(2):175–184. doi: 10.1016/s0092-8674(00)80197-x. [DOI] [PubMed] [Google Scholar]
- Lu X. P., Fanjul A., Picard N., Pfahl M., Rungta D., Nared-Hood K., Carter B., Piedrafita J., Tang S., Fabbrizio E. Novel retinoid-related molecules as apoptosis inducers and effective inhibitors of human lung cancer cells in vivo. Nat Med. 1997 Jun;3(6):686–690. doi: 10.1038/nm0697-686. [DOI] [PubMed] [Google Scholar]
- Mangelsdorf D. J., Thummel C., Beato M., Herrlich P., Schütz G., Umesono K., Blumberg B., Kastner P., Mark M., Chambon P. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec 15;83(6):835–839. doi: 10.1016/0092-8674(95)90199-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martin S. J., Amarante-Mendes G. P., Shi L., Chuang T. H., Casiano C. A., O'Brien G. A., Fitzgerald P., Tan E. M., Bokoch G. M., Greenberg A. H. The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism. EMBO J. 1996 May 15;15(10):2407–2416. [PMC free article] [PubMed] [Google Scholar]
- Martin S. J., Green D. R. Protease activation during apoptosis: death by a thousand cuts? Cell. 1995 Aug 11;82(3):349–352. doi: 10.1016/0092-8674(95)90422-0. [DOI] [PubMed] [Google Scholar]
- Martin S. J., O'Brien G. A., Nishioka W. K., McGahon A. J., Mahboubi A., Saido T. C., Green D. R. Proteolysis of fodrin (non-erythroid spectrin) during apoptosis. J Biol Chem. 1995 Mar 24;270(12):6425–6428. doi: 10.1074/jbc.270.12.6425. [DOI] [PubMed] [Google Scholar]
- Memon S. A., Moreno M. B., Petrak D., Zacharchuk C. M. Bcl-2 blocks glucocorticoid- but not Fas- or activation-induced apoptosis in a T cell hybridoma. J Immunol. 1995 Nov 15;155(10):4644–4652. [PubMed] [Google Scholar]
- Miura M., Friedlander R. M., Yuan J. Tumor necrosis factor-induced apoptosis is mediated by a CrmA-sensitive cell death pathway. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8318–8322. doi: 10.1073/pnas.92.18.8318. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miura M., Zhu H., Rotello R., Hartwieg E. A., Yuan J. Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 1993 Nov 19;75(4):653–660. doi: 10.1016/0092-8674(93)90486-a. [DOI] [PubMed] [Google Scholar]
- Muzio M., Chinnaiyan A. M., Kischkel F. C., O'Rourke K., Shevchenko A., Ni J., Scaffidi C., Bretz J. D., Zhang M., Gentz R. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996 Jun 14;85(6):817–827. doi: 10.1016/s0092-8674(00)81266-0. [DOI] [PubMed] [Google Scholar]
- Nicholson D. W., Ali A., Thornberry N. A., Vaillancourt J. P., Ding C. K., Gallant M., Gareau Y., Griffin P. R., Labelle M., Lazebnik Y. A. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37–43. doi: 10.1038/376037a0. [DOI] [PubMed] [Google Scholar]
- Noti J. D., Reinemann B. C., Petrus M. N. Sp1 binds two sites in the CD11c promoter in vivo specifically in myeloid cells and cooperates with AP1 to activate transcription. Mol Cell Biol. 1996 Jun;16(6):2940–2950. doi: 10.1128/mcb.16.6.2940. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Perkins N. D., Edwards N. L., Duckett C. S., Agranoff A. B., Schmid R. M., Nabel G. J. A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation. EMBO J. 1993 Sep;12(9):3551–3558. doi: 10.1002/j.1460-2075.1993.tb06029.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pfahl M., Apfel R., Bendik I., Fanjul A., Graupner G., Lee M. O., La-Vista N., Lu X. P., Piedrafita J., Ortiz M. A. Nuclear retinoid receptors and their mechanism of action. Vitam Horm. 1994;49:327–382. doi: 10.1016/s0083-6729(08)61150-4. [DOI] [PubMed] [Google Scholar]
- Piedrafita F. J., Bendik I., Ortiz M. A., Pfahl M. Thyroid hormone receptor homodimers can function as ligand-sensitive repressors. Mol Endocrinol. 1995 May;9(5):563–578. doi: 10.1210/mend.9.5.7565804. [DOI] [PubMed] [Google Scholar]
- Piedrafita F. J., Molander R. B., Vansant G., Orlova E. A., Pfahl M., Reynolds W. F. An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem. 1996 Jun 14;271(24):14412–14420. doi: 10.1074/jbc.271.24.14412. [DOI] [PubMed] [Google Scholar]
- Rasnick D. Synthesis of peptide fluoromethyl ketones and the inhibition of human cathepsin B. Anal Biochem. 1985 Sep;149(2):461–465. doi: 10.1016/0003-2697(85)90598-6. [DOI] [PubMed] [Google Scholar]
- Sarin A., Wu M. L., Henkart P. A. Different interleukin-1 beta converting enzyme (ICE) family protease requirements for the apoptotic death of T lymphocytes triggered by diverse stimuli. J Exp Med. 1996 Dec 1;184(6):2445–2450. doi: 10.1084/jem.184.6.2445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shao Z. M., Dawson M. I., Li X. S., Rishi A. K., Sheikh M. S., Han Q. X., Ordonez J. V., Shroot B., Fontana J. A. p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. Oncogene. 1995 Aug 3;11(3):493–504. [PubMed] [Google Scholar]
- Song Q., Lees-Miller S. P., Kumar S., Zhang Z., Chan D. W., Smith G. C., Jackson S. P., Alnemri E. S., Litwack G., Khanna K. K. DNA-dependent protein kinase catalytic subunit: a target for an ICE-like protease in apoptosis. EMBO J. 1996 Jul 1;15(13):3238–3246. [PMC free article] [PubMed] [Google Scholar]
- Spector M. S., Desnoyers S., Hoeppner D. J., Hengartner M. O. Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature. 1997 Feb 13;385(6617):653–656. doi: 10.1038/385653a0. [DOI] [PubMed] [Google Scholar]
- Srinivasula S. M., Ahmad M., Fernandes-Alnemri T., Litwack G., Alnemri E. S. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14486–14491. doi: 10.1073/pnas.93.25.14486. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Steller H. Mechanisms and genes of cellular suicide. Science. 1995 Mar 10;267(5203):1445–1449. doi: 10.1126/science.7878463. [DOI] [PubMed] [Google Scholar]
- Tewari M., Dixit V. M. Fas- and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus crmA gene product. J Biol Chem. 1995 Feb 17;270(7):3255–3260. doi: 10.1074/jbc.270.7.3255. [DOI] [PubMed] [Google Scholar]
- Tewari M., Quan L. T., O'Rourke K., Desnoyers S., Zeng Z., Beidler D. R., Poirier G. G., Salvesen G. S., Dixit V. M. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 1995 Jun 2;81(5):801–809. doi: 10.1016/0092-8674(95)90541-3. [DOI] [PubMed] [Google Scholar]
- Thome M., Schneider P., Hofmann K., Fickenscher H., Meinl E., Neipel F., Mattmann C., Burns K., Bodmer J. L., Schröter M. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature. 1997 Apr 3;386(6624):517–521. doi: 10.1038/386517a0. [DOI] [PubMed] [Google Scholar]
- Thornberry N. A., Bull H. G., Calaycay J. R., Chapman K. T., Howard A. D., Kostura M. J., Miller D. K., Molineaux S. M., Weidner J. R., Aunins J. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992 Apr 30;356(6372):768–774. doi: 10.1038/356768a0. [DOI] [PubMed] [Google Scholar]
- Voelkel-Johnson C., Entingh A. J., Wold W. S., Gooding L. R., Laster S. M. Activation of intracellular proteases is an early event in TNF-induced apoptosis. J Immunol. 1995 Feb 15;154(4):1707–1716. [PubMed] [Google Scholar]
- Wang L., Miura M., Bergeron L., Zhu H., Yuan J. Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell. 1994 Sep 9;78(5):739–750. doi: 10.1016/s0092-8674(94)90422-7. [DOI] [PubMed] [Google Scholar]
- Wang X., Zelenski N. G., Yang J., Sakai J., Brown M. S., Goldstein J. L. Cleavage of sterol regulatory element binding proteins (SREBPs) by CPP32 during apoptosis. EMBO J. 1996 Mar 1;15(5):1012–1020. [PMC free article] [PubMed] [Google Scholar]
- White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
- Xue D., Horvitz H. R. Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein. Nature. 1995 Sep 21;377(6546):248–251. doi: 10.1038/377248a0. [DOI] [PubMed] [Google Scholar]
- Xue D., Shaham S., Horvitz H. R. The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. Genes Dev. 1996 May 1;10(9):1073–1083. doi: 10.1101/gad.10.9.1073. [DOI] [PubMed] [Google Scholar]
- Yonehara S., Ishii A., Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989 May 1;169(5):1747–1756. doi: 10.1084/jem.169.5.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yuan J. Y., Horvitz H. R. The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death. Dev Biol. 1990 Mar;138(1):33–41. doi: 10.1016/0012-1606(90)90174-h. [DOI] [PubMed] [Google Scholar]
- Yuan J., Shaham S., Ledoux S., Ellis H. M., Horvitz H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993 Nov 19;75(4):641–652. doi: 10.1016/0092-8674(93)90485-9. [DOI] [PubMed] [Google Scholar]