Summary
TRAIL and its emerging receptors are the newest members of the TNF receptor super-family. The activation of TRAIL receptors by ligand binding leads to apoptosis through caspase activation through an as yet unclear signaling pathway that does not require the FADD adaptor. The TRAIL receptor KILLER/DR5, is induced by DNA damage and appears to be regulated by the tumor suppressor gene p53. Both the Fas receptor and KILLER/DR5 provide potential links between DNA damage-mediated activation of the p53 tumor suppressor and caspase activation. While further evaluation of the role of TRAIL receptors in human cancer is ongoing, initial studies suggest that both KILLER/DR5 and DR4 may be targets for inactivation and that these pro-apooptotic receptors may be tumro suppressor genes. Understanding the regulation of TRAIL and its receptors may thus be beneficial for the development of novel approaches for cancer treatment. TRAIL appears to be a cancer-specific cytotoxic agent and thus offers promise as a novel therapy for cancer either through replacement of the cytokine or potentially via gene replacement. Preliminary studies suggest the potential to combine TRAIL with classical cytotoxic chemotherapeutic drugs to achieve synergistic cell killing.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Ashkenazi, A., and Dixit, V.M., 1998, Death receptors: signaling and modulation, Science 281:1305–1308.
Bedi, A., Ravi, R., Engstrom, L.W., Wu, G.S., Yeh, W.-C, Mak, T.W., El-Deiry, W.S., and Fuchs, E.J., 1998, Fas (CD95)-independent, p53-mediated apoptosis, submitted.
Bennett, M., Macdonald, K., Chan, S.W., Luzio, J.P., Simari, P., and Weissberg, P., 1998, Cell surface trafficking of Fas: A rapid mechanism of p53-mediated apoptosis, Science 282:290–293.
Boldin, M.P., Mett, I.L., Varfolomeev, E.E., Chumakov, I., Shemer-Avni, Y., Camonis, J.H., and Wallach, D., 1995, Self-association of the “death-domains” of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects, J. Biol. Chem. 270:387–391.
Boldin, M.P., Varfolomeev, E.E., Pancer, Z., Mett, I.L., Camonis, J.H., and Wallach, D., 1995, A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain, J. Biol. Chem. 270:7795–7798.
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J.P., Sedivy, J.M., Kinzler, K.W., and Vogelstein, B., 1998, Requirement for p53 and p21 to sustain G2 arrest after DNA damage, Science 282:149–150.
Chaudhary, P.M., Eby, M., Jasmin, A., Bookwalter, A., Murray, J., and Hood, L., 1997, Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kB pathway, Immunity 7:821–830.
Chinnaiyan, A.M., O’Rourke, K., Tewari, M., and Dixit, V.M., 1995, FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis, Cell 81:505–512.
Clarke, A.R., Purdie, C.A., Harrison, D.J., Morris, R.G., Bird, C.C., Hooper, M.L., and Wyllie, A.H., 1993, Thymocyte apoptosis induced by p53-dependent and independent pathways, Nature 362:849–852.
El-Deiry, W.S., 1998, The p53 pathway and cancer therapy, The Cancer J. 11:229–236.
Golstein, P., 1997, Cell death: TRAIL and its receptors, Curr. Biol. 7:R750–R753.
Goodwin, R.G., and Smith, C.A., 1998, The TRAIL of death, Apoptosis 3:83–88.
Griffith, T.S., Chin, W.A., Jackson, G.C., Lynch, D.H., and Kubin, M.Z.,1998, Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells, J. Immunol 161:2833–2840.
Hsu, H., Xiong, J., and Goeddel, D.V., 1995, The TNF receptor 1-associated protein TRADD signals cell death and NF-kB activation, Cell 81:495–504.
Hopkin, K., 1997, For p53, there’s more than one way to kill a cell, J. NIH Res. 9:22–24.
Itoh, N., Yonehara, S., Ishii, A., Yonehara, M., Mizushima, S., Sameshima, M., Hase, A., Seto, Y., and Nagata, S., 1991, The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis, Cell 66:233–243.
Kastan, M., 1997, On the TRAIL from p53 to apoptosis?, Nature Genet. 17:130–131.
Kerr, J. F.R., Wyllie, A.H., and Currie, A.R., 1972, Apoptosis: A Basic Biological Phenomenon with Wide-Ranging Implications in Tissue Kinetics, Br. J. Cancer 26:239–257.
Kim, K.H., and El-Deiry, W.S., 1998, Molecular determinants of response to TRAIL combined with chemotherapy in killing of normal and cancer cells, submitted.
Knudson, C.M., Tung, K.S., Tourlellotte, W.G., Brown, G.A., and Korsmeyer, S.J., 1995, Bax-deficient mice with lymphoid hyperplasia and male germ cell death, Science 270:96–99.
Levine, A.J., 1997, p53, the cellular gatekeeper for growth and division, Cell 88:323–331.
MacFarlane, M., Ahmad, M., Srinivasula, S.M., Fernandes-Alnemri, T., Cohen, G.M., and Alnemri, E., 1997, Identification and molecular cloning of two novel receptors for cytotoxic ligand TRAIL, J. Biol. Chem. 272:25417–25420.
Marsters, S.A., Pitti, R.M., Donahue, C.J., Ruppert, S., Bauer, K.D., and Ashkenazi, A., 1996, Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA, Curr. Biol. 6:750–752.
Marsters, S.A., Sheridan, J.P., Pitti, R.M., Huang, A., Skubatch, M., Baldwin, D., Yuan, J., Gurney, A., Goddard, A.D., Godowski, P., and Ashkenazi, A., 1997, A novel receptor for Apo2L/TRAIL contains a truncated death domain, Curr. Biol. 7:1003–1006.
McCurrach, M.E., Connor, T.M., Knudson, C.M., Korsmeyer, S.J., and Lowe, S.W., 1997, bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis, Proc. Natl. Acad. U.S.A. 94:2345–2349.
Miller, T.M., Moulder, K.L., Knudson, C.M., Creedon, D.J., Deshmukh, M., Korsmeyer, S.J., and Johnson, E.M. Jr., 1997, Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death, J. Cell Biol. 139:205–217.
Mitelman, F., Mertens, F., and Johansson, B., 1997, A breakpoint map of recurrent chromosomal rearrangements in human neoplasia, Nature Genet. 15:417–474.
Miyashita, T., Krajewski, S., Krajewski, M., Wang, H.G., Lin, H.K., Liebermann, D., Hoffman, B., and Reed, J.C., 1994, Tumor suppressor p53 is a regulator of bc12 and bax gene expression in vitro and in vivo, Oncogene 9:1799–1805.
Miyashita, T., and Reed, J.C., 1995, Tumor suppressor p53 is a direct transcriptional activator of human bax gene, Cell 80:293–299.
Nagata, S., 1997, Apoptosis by death factor, Cell 88:355–365.
Ogasawara, J., Watanabe-Fukunaga, R., Adachi, M., Matsuzawa, A., Kasugai, T., Kitamura, Y., Itoh, N., Suda, T., and Nagata, S., 1993, Lethal effect of the anti-Fas antibody in mice, Nature 364:806–809.
Owen-Schaub, L.B., Zhang, W., Cusack, J.C., Angelo, L.S., Santee, S.M., Fujiwara, T., Roth, J.A., Deisseroth, A.B., Zhang, W.W., and Kruzel, E., 1995, Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression, Mol. Cell Biol. 15:3032–3040.
Ozoren, N., Fisher, M.J., Kim, K.H., Liu, C.X., Lisitsyn, N.A., and El-Deiry, W.S., 1998, Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance, submitted.
Pai, S.I., Wu, G.S., Ozoren, N., Wu, L., Jen, J., Sidransky, D., and El-Deiry, W.S., 1998, Rare loss-of-function mutation of a death receptor gene in head and neck cancer, Cancer Res. 58:3513–1318.
Pan, G., O’Rourke, K., Chinnaiyan, A.M., Gentz, R., Ebner, R., Ni, J., and Dixit, V.M., 1997a, The receptor for the cytotoxic ligand TRAIL, Science 276:111–113.
Pan, G., Ni, J., Wei, Y.F., Yu, G., Gentz, R., and Dixit, V.M. An antagonist decoy receptor and a death domain-containing receptor for TRAIL., 1997b, Science 277:815–818.
Pan, G., Ni, J., Yu, G., Wei, Y.F., and Dixit, V.M., 1998, TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling, FEBS Letters 424:41–45.
Pitti, R.M., Marsters, S.A., Ruppert, S., Donahue, C.J., Moore, A., and Ashkenazi, A., 1996, Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family, J. Biol. Chem. 271:12687–12690.
Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W., and Vogelstein, B., 1997, A model for p53-induced apoptosis, Nature 389:300–305.
Rieger, J., Naumann, U., Glaser, T., Ashkenazi, A., and Weller, M., 1998, APO2 ligand: a novel lethal weapon against malignant glioma?, FEBS Letters 427:124–128.
Schneider, P., Bodmer, J.L., Thome, M., Hofmann, K., Holler, N., and Tschopp, J., 1997a, Characterization of two receptors for TRAIL, FEBS Letters 416:329–334.
Schneider, P., Thome, M., Burns, K., Bodmer, J.L., Hofmann, K., Kataoka, T., Holler, N., and Tschopp, J., 1997b, TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-κB, Immunity 7:831–836.
Screaton, G.R., Mongkolsapaya, J., Xu, X.N., Cowper, A.E., McMichael, A.J., and Bell, J., 1997, TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signals from TRAIL, Curr. Biol. 7:693–696.
Sheridan, J.P., Marsters, S.A., Pitti, R.M., Gurney, A., Skubatch, M., Baldwin, D., Ramakrishnan, L., Gray, C.L., Baker, K., Wood, W.I., Goddard, A.D., Godowski, P., and Ashkenazi, A., 1997, Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors, Science 277:818–821.
Sun, S.-Y., Yue, P., Wu, G.S., EI-Deiry, W.S., Shroot, B., Hong, W.K., and Lotan, R., 1998, Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells, Oncogene, in press.
Thomas, W.D., and Hersey, P., 1998, TNF-relating apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells, J. Immnol. 161-:2195–2200.
Walczak, H., Degli-Espositi, M.A., Johnson, R.S., Smolak, P.J., Waugh, J.Y., Boiani, N., Timour, M.S., Gerhart, M.J., Schooley, K.A., Smith, C.A., Goodwin, R.G., and Rauch, C.T., 1997, TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL, EMBO J. 16:5386–5397.
Wiley, S.R., Schooley, K., Smolak, P.J., Din, W.S., Huang, C.-P, Nicholl, J.K., Sutherland, G.R., Smith. T.D., Rauch, C., Smith, C.A., and Goodwin, R.G., 1995, Identification and characterization of a new member of the TNF family that induces apoptosis, Immunity 3:673–682.
Wu, G.S., Burns, T.F., McDonald, E.R., III, Jiang, W., Meng, R., Krantz, I.D., Kao, G., Gan, D.-D., Zhou, J.-Y., Muschel, R., Hamilton, S.R., Spinner, N.B., Markowitz, S., Wu, G., and El-Deiry, W.S., 1997, KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene, Nature Genet. 17: 141–143.
Wu, G.S., Burns, T.F., Meng, R.D., and El-Deiry, W.S., 1998, Involvement of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest, submitted.
Yen, W.C., Pompa, J.L., McCurrach, M.E., Shu, H.B., Elia, A.J., Shahinian, A., Ng, M., Wakeham, A., Khoo, W., Mitchell, K., El-Deiry, W.S., Lowe, S.W., Goeddel, D.V., and Mak, T.W., 1998, FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis, Science 279-:1954–1958.
Yuan, J., Shaham, S., Ledoux, S., Ellis, H.M., and Horvitz, H.R., 1993, The C. elegans cell death gene ced-3 encodes a protein similar to mammalianinterleukin-1β-converting enzyme, Cell 75:641–652.
Yuan, J., 1997, Transducing signals of life and death, Curr. Opin. in Cell Biol. 9:247–251.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Kluwer Academic Publishers
About this chapter
Cite this chapter
Wu, G.S., Kim, K., El-Deiry, W.S. (2002). Killer/DR5, A Novel DNA-Damage Inducible Death Receptor Gene, Links the p53-Tumor Suppressor to Caspase Activation and Apoptotic Death. In: Habib, N.A. (eds) Cancer Gene Therapy. Advances in Experimental Medicine and Biology, vol 465. Springer, New York, NY. https://doi.org/10.1007/0-306-46817-4_13
Download citation
DOI: https://doi.org/10.1007/0-306-46817-4_13
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-306-46191-0
Online ISBN: 978-0-306-46817-9
eBook Packages: Springer Book Archive