Autophagy is a process by which the cell recycles its components through self-consumption of cellular organelles and bulk cytoplasm. In times of stress, it serves to generate much needed nutrients. When overactivated, however, the orderly destruction of organelles can lead to cell death. At times, autophagic cell death is used as an alternative to apoptosis to eliminate unwanted, damaged, or transformed cells. Consistent with this, tumorigenesis is associated with a downregulation in autophagy, and genes that mediate the execution of the process have been shown to be tumor suppressors. At the same time, basal autophagy has been harnessed by some tumor cells as a survival mechanism to protect against ischemia and signals that induce apoptosis. Thus, the relationship between autophagy and tumor development is complex. Here, we discuss the basic machinery of mammalian autophagy and its regulators, with specific emphasis on those genes that have been linked to cancer. Research supporting the divergent nature of autophagy in both tumor suppression and tumor progression is presented. We conclude with a survey of recent approaches to treating cancer with strategies that modulate autophagy.
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References
Abeliovich, H., Zhang, C., Dunn, W. A., Jr., Shokat, K. M., and Klionsky, D. J. (2003). Chemical genetic analysis of Apg1 reveals a non-kinase role in the induction of autophagy. Mol Biol Cell 14, 477–490.
Aita, V. M., Liang, X. H., Murty, V. V., Pincus, D. L., Yu, W., Cayanis, E., Kalachikov, S., Gilliam, T. C., and Levine, B. (1999). Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 59, 59–65.
Anjum, R., Roux, P. P., Ballif, B. A., Gygi, S. P., and Blenis, J. (2005). The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling. Curr Biol 15, 1762–1767.
Aplin, A., Jasionowski, T., Tuttle, D. L., Lenk, S. E., and Dunn, W. A., Jr. (1992). Cytoskeletal elements are required for the formation and maturation of autophagic vacuoles. J Cell Physiol 152, 458–466.
Bauvy, C., Gane, P., Arico, S., Codogno, P., and Ogier-Denis, E. (2001). Autophagy delays sulindac sulfide-induced apoptosis in the human intestinal colon cancer cell line HT-29. Exp Cell Res 2682, 139–149.
Bertwistle, D., Sugimoto, M., and Sherr, C. J. (2004). Physical and functional interactions of the arf tumor suppressor protein with nucleophosmin/b23. Mol Cell Biol 24, 985–996.
Bialik, S. and Kimchi, A. (2004). DAP-kinase as a target for drug design in cancer and diseases associated with accelerated cell death, Semin. Cancer Biol 14, 283–294.
Bialik, S. and Kimchi, A. (2006). The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem 75, 189–210.
Bialik, S., Bresnick, A. R., and Kimchi, A. (2004). DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation. Cell Death Differ 11, 631–644.
Boya, P., Gonzalez-Polo, R. A., Casares, N., Perfettini, J. L., Dessen, P., Larochette, N., Metivier, D., Meley, D., Souquere, S., Yoshimori, T., Pierron, G., Codogno, P., and Kroemer, G. (2005). Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 25, 1025–1040.
Bursch, W. (2001). The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 8, 569–581.
Bursch, W., Ellinger, A., Kienzl, H., Torok, L., Pandey, S., Sikorska, M., Walker, R., and Hermann, R. S. (1996). Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 17, 1595–1607.
Cardenas-Aguayo Mdel, C., Santa-Olalla, J., Baizabal, J. M., Salgado, L. M., and Covarrubias, L. (2003). Growth factor deprivation induces an alternative non-apoptotic death mechanism that is inhibited by Bcl2 in cells derived from neural precursor cells. J Hematother Stem Cell Res 12, 735–748.
Chen, C. H., Wang, W. J., Kuo, J. C., Tsai, H. C., Lin, J. R., Chang, Z. F., Chen, R. H. (2005a). Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J 24, 294–304.
Chen, Y., Yang, L., Feng, C., and Wen, L. P. (2005b). Nano neodymium oxide induces massive vacuolization and autophagic cell death in non-small cell lung cancer NCI-H460 cells. Biochem Biophys Res Commun 337, 52–60.
Chi, S., Kitanaka, C., Noguchi, K., Mochizuki, T., Nagashima, Y., Shirouzu, M., Fujita, H., Yoshida, M., Chen, W., Asai, A., Himeno, M., Yokoyama, S., and Kuchino, Y. (1999). Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. Oncogene 18, 2281–2290.
Clarke, P. G. (1990). Developmental cell death: morphological diversity and multiple mechanisms. Anat Embyol 181, 195–213.
Cohen, O., Feinstein, E., and Kimchi, A. (1997). DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. EMBO J 16, 998–1008.
Crighton, D., Wilkinson, S., O’Prey, J., Syed, N., Smith, P., Harrison, P. R., Gasco, M., Garrone, O., Crook T, and Ryan, K. M. (2006). DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134.
Cuervo, A. M. (2004). Autophagy: in sickness and in health. Trends Cell Biol 14, 70–77.
Degenhardt, K., Mathew, R., Beaudoin, B., Bray, K., Anderson, D., Chen, G., Mukherjee, C., Shi, Y., Gelinas, C., Fan, Y., Nelson, D. A., Jin, S., and White, E. (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51–64.
Deiss, L., Feinstein, E., Berissi, H., Cohen, O., and Kimchi, A. (1995). Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 9, 15–30.
Djavaheri-Mergny, M., Amelotti, M., Mathieu, J., Besancon, F., Bauvy, C., Souquere, S., Pierron, G., and Codogno, P. (2006). NF-kappa B activation represses TNF alpha-induced autophagy. J Biol Chem 281, 34870–34879.
Feng, Z., Zhang, H., Levine, A. J., and Jin, S. (2005). The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102, 8204–8209.
Fingar, D. C. and Blenis, J. (2004). Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23, 3151–3171.
Gajewska, M., Gajkowska, B., and Motyl, T. (2005). Apoptosis and autophagy induced by TGF-B1 in bovine mammary epithelial BME-UV1 cells. J Physiol Pharmacol 6S3, 143–157.
Gillooly, D. J., Simonsen, A., and Stenmark, H. (2001). Cellular functions of phosphatidylinositol 3-phosphate and FYVE domain proteins. Biochem J 355, 249–258.
Gorka, M., Daniewski, W. M., Gajkowska, B., Lusakowska, E., Godlewski, M. M., and Motyl, T. (2005). Autophagy is the dominant type of programmed cell death in breast cancer MCF-7 cells exposed to AGS 115 and EFDAC, new sesquiterpene analogs of paclitaxel. Anticancer Drugs 16, 777–788.
Gozuacik, D. and Kimchi, A. (2004). Autophagy as a cell death and tumor suppressor mechanism. Oncogene 2, 2891–2906.
Gronostajski, R. M. and Pardee, A. B. (1984). Protein degradation in 3T3 cells and tumorigenic transformed 3T3 cells. J Cell Physiol 119, 127–132.
Gunn, J. M., Clark, M. G., Knowles, S. E., Hopgood, M. F., and Ballard, F. J. (1977). Reduced rates of proteolysis in transformed cells. Nature 266, 58–60.
Hahn-Windgassen, A., Nogueira, V., Chen, C. C., Skeen, J. E., Sonenberg, N., and Hay, N. (2005). Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280, 32081–32089.
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., and Mizushima, N. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889.
Harding, T. M., Morano, K. A., Scott, S. V., and Klionsky, D. J. (1995). Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol 131, 591–602.
Herman-Antosiewicz, A., Johnson, D. E., and Singh, S. V. (2006). Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells. Cancer Res 66, 5828–5835.
Hoyer-Hansen, M., Bastholm, L., Mathiasen, I. S., Elling, F., and Jaattela, M. (2005). Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ 12, 1297–1309.
Huang, W. P. and Klionsky, D. J. (2002). Autophagy in yeast: a review of the molecular machinery. Cell Struct Funct 27, 409–420.
Ichimura, Y., Kirisako, T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., Noda, T., and Ohsumi, Y. (2000). A ubiquitin-like system mediates protein lipidation. Nature 408, 488–492.
Inbal, B., Cohen, O., Polak-Charcon, S., Kopolovic, J., Vadai, E., Eisenbach, L., and Kimchi, A. (1997). DAP kinase links the control of apoptosis to metastasis. Nature 390, 180–184.
Inbal, B., Bialik, S., Sabanay, I., Shani, G., and Kimchi, A. (2002). DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol 157, 455–468.
Inoki, K., Li, Y., Zhu, T., Wu, J., and Guan, K. L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol 4, 648–657.
Inoki, K., Zhu, T., and Guan, K. L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590.
Ito, H., Daido, S., Kanzawa, T., Kondo, S., and Kondo, Y. (2005). Radiation-induced autophagy is associated with LC3 and its inhibition sensitizes malignant glioma cells. Int J Oncol 26, 1401–1410.
Ito, H., Aoki, H., Kuhnel, F., Kondo, Y., Kubicka, S., Wirth, T., Iwado, E., Iwamaru, A., Fujiwara, K., Hess, K. R., Lang, F. F., Sawaya, R., and Kondo, S. (2006). Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus. J Natl Cancer Inst 98, 625–636.
Jia, L., Dourmashkin, R. R., Allen, P. D., Gray, A. B., Newland, A. C., and Kelsey, S. M. (1997). Inhibition of autophagy abrogates tumour necrosis factor alpha induced apoptosis in human T-lymphoblastic leukaemic cells. Br J Haematol 98, 673–685.
Kamada, Y., Funakoshi, T., Shintani, T., Nagano, K., Ohsumi, M., and Ohsumi, Y. (2000). Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150, 1507–1513.
Kanzawa, T., Kondo, Y., Ito, H., Kondo, S., and Germano, I. (2003). Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 63, 2103–2108.
Kanzawa, T., Zhang, L., Xiao, L., Germano, I. M., Kondo, Y., and Kondo, S. (2004). Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Cell Death Differ 11, 448–457.
Kihara, A., Kabeya, Y., Ohsumi, Y., and Yoshimori, T. (2001). Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep 2, 330–335.
Kim, R. H. and Mak, T. W. (2006). Tumours and tremors: how PTEN regulation underlies both. Br J Cancer 94, 620–624.
Kim, J., Huang, W. P., Stromhaug, P. E., and Klionsky, D. J. (2002). Convergence of multiple autophagy and cytoplasm to vacuole targeting components to a perivacuolar membrane compartment prior to de novo vesicle formation. J Biol Chem 277, 763–773.
Kirisako, T., Baba, M., Ishihara, N., Miyazawa, K., Ohsumi, M., Yoshimori, T., Noda, T., and Ohsumi, Y. (1999). Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol 147, 435–446.
Kirisako, T., Ichimura, Y., Okada, H., Kabeya, Y., Mizushima, N., Yoshimori, T., Ohsumi, M., Takao, T., Noda, T., and Ohsumi, Y. (2000). The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol 151, 263–276.
Kisen, G. O., Tessitore, L., Costelli, P., Gordon, P. B., Schwarze, P. E., Baccino, F. M., and Seglen, P. O. (1993). Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis 14, 2501–2505.
Klionsky, D. J., Cregg, J. M., Dunn, W. A., Jr., Emr, S. D., Sakai, Y., Sandoval, I. V., Sibirny, A., Subramani, S., Thumm, M., Veenhuis, M., and Ohsumi, Y. (2003). A unified nomenclature for yeast autophagy-related genes. Dev Cell 5, 539–545.
Knecht, E., Hernandez-Yago, J., and Grisolia, S. (1984). Regulation of lysosomal autophagy in transformed and non-transformed mouse fibroblasts under several growth conditions. Exp Cell Res 154, 224–232.
Kochl, R., Hu, X. W., Chan, E. Y., and Tooze, S. A. (2006). Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 7, 129–145.
Komatsu, S. and Ikebe, M. (2004). ZIP kinase is responsible for the phosphorylation of myosin II and necessary for cell motility in mammalian fibroblasts. J Cell Biol 165, 243–254.
Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., Kominami, E., Tanaka, K., and Chiba, T. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169, 425–434.
Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., and Tanaka, K. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884.
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., and Mizushima, N. (2004). The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036.
Kuo, J. C., Lin, J. R., Staddon, J. M., Hosoya, H., and Chen, R. H. (2003). Uncoordinated regulation of stress fibers and focal adhesions by DAP kinase. J Cell Sci 116, 4777–4790.
Kwiatkowski, D. J. and Manning, B. D. (2005). Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 14, R251–R258.
Lamparska-Przybysz, M., Gajkowska, B., and Motyl, T. (2005). Cathepsins and BID are involved in the molecular switch between apoptosis and autophagy in breast cancer MCF-7 cells exposed to camptothecin. J Physiol Pharmacol 56 (Suppl 3), 159–179.
Lefranc, F. and Kiss, R. (2006). Autophagy, the Trojan horse to combat glioblastomas, Neurosurg. Focus 20, E7.
Liang, X. H., Kleeman, L. K., Jiang, H. H., Gordon, G., Goldman, J. E., Berry, G., Herman, B., and Levine, B. (1998). Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72, 8586–8596.
Liang, X. H., Jackson, S., Seaman, M., Brown, K., Kempkes, B., Hibshoosh, H., and Levine, B. (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676.
Liang, C., Feng, P., Ku, B., Dotan, I., Canaani, D., Oh, B. H., and Jung, J. U. (2006). Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nature Cell Biol 8, 688–699.
Lowe, S. W. and Sherr, C. J. (2003). Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 13, 77–83.
Lum, J. J., Bauer, D. E., Kong, M., Harris, M. H., Li, C., Lindsten, T., and Thompson, C. B. (2005). Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237–248.
Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., and Pandolfi, P. P. (2005). Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193.
Martoriati, A., Doumont, G., Alcalay, M., Bellefroid, E., Pelicci, P. G., and Marine, J. C. (2005). Dapk1, encoding an activator of a p19ARF-p53-mediated apoptotic checkpoint, is a transcription target of p53. Oncogene 24, 1461–1466.
Mills, K. R., Reginato, M., Debnath, J., Queenan, B., and Brugge, J. S. (2004). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc Natl Acad Sci USA 101, 3438–3443.
Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M. D., Klionsky, D. J., Ohsumi, M., and Ohsumi, Y. (1998). A protein conjugation system essential for autophagy. Nature 395, 395–398.
Mizushima, N., Noda, T., and Ohsumi, Y. (1999). Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J 18, 3888–3896.
Mizushima, N., Yamamoto, A., Hatano, M., Kobayashi, Y., Kabeya, Y., Suzuki, K., Tokuhisa, T., Ohsumi, Y., and Yoshimori, T. (2001). Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152, 657–668.
Mizushima, N., Kuma, A., Kobayashi, Y., Yamamoto, A., Matsubae, M., Takao, T., Natsume, T., Ohsumi, Y., and Yoshimori, T. (2003). Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci 116, 1679–1688.
Murata-Hori, M., et al. (2001). HeLa ZIP kinase induces diphosphorylation of myosin II regulatory light chain and reorganization of actin filaments in nonmuscle cells. Oncogene 20, 8175–8183.
Natarajan, K., Meyer, M. R., Jackson, B. M., Slade, D., Roberts, C., Hinnebusch, A. G., and Marton, M. J. (2001). Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol Cell Biol 21, 4347–4368.
Ng, G. and Huang, J. (2005). The significance of autophagy in cancer. Mol Carcinogenesis 43, 183–187.
Page, G., Kogel, D., Rangnekar, V., and Scheidtmann, K. H. (1999). Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis. Oncogene 18, 7265–7273.
Paglin, S., Hollister, T., Delohery, T., Hackett, N., McMahill, M., Sphicas, E., Domingo, D., and Yahalom, J. (2001). A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res. 61, 439–444.
Pattingre, S., Tassa, A., Qu, X., Garuti, R., Liang, X. H., Mizushima, N., Packer, M., Schneider, M. D., and Levine, B. (2005). Bcl-2 antiapoptotic proteins inhibit beclin 1-dependent autophagy. Cell 122, 927–939.
Pelkmans, L, Pelkmans, L., Fava, E., Grabner, H., Hannus, M., Habermann, B., Krausz, E., and Zerial, M. (2005). Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436, 78–86.
Petiot, A., Ogier-Denis, E., Blommaart, E. F., Meijer, A. J., and Codogno, P. (2000). Distinct classes of phosphatidylinositol 3’-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 275, 992–998.
Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E. L., Mizushima, N., Ohsumi, Y., Cattoretti, G., and Levine, B. (2003). Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112, 1809–1820.
Raveh, T., Droguett, G., Horwitz, M. S., DePinho, R. A., and Kimchi, A. (2001). DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol 3, 1–7.
Reef, S., Zalckvar, E., Shifman, O., Bialik, S., Sabanay, H., Oren, M., and Kimchi, A. (2006). A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol Cell 22, 463–475.
Roux, P. P., Ballif, B. A., Anjum, R., Gygi, S. P., and Blenis, J. (2004). Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 101, 13489–13494.
Saeki, K., You, A., Okuma, E., Yazaki, Y., Susin, S. A., Kroemer, G., Takaku, F. (2000). Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells. Cell Death Differ 7, 1263–1269.
Samuels, Y. and Ericson, K. (2006). Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18, 77–82.
Sarbassov dos, D., Ali, S. M., and Sabatini, D. M. (2005). Growing roles for the mTOR pathway. Curr Opin Cell Biol 17, 596–603.
Schweichel, J. U. and Merker, H. J. (1973). The morphology of various types of cell death in prenatal tissues. Teratology 7, 253–266.
Scott, S. V., Nice, D. C., III, Nau, J. J., Weisman, L. S., Kamada, Y., Keizer-Gunnink, I., Funakoshi, T., Veenhuis, M., Ohsumi, Y., and Klionsky, D. J. (2000). Apg13p and Vac8p are part of a complex of phosphoproteins that are required for cytoplasm to vacuole targeting. J Biol Chem 275, 25840–25849.
Shani, G., Marash, L., Gozuacik, D., Bialik, S., Teitelbaum, L., Shohat, G., and Kimchi, A. (2004). Death-associated protein kinase phosphorylates ZIP kinase, forming a unique kinase hierarchy to activate its cell death functions. Mol Cell Biol 24, 8611–8626.
Shao, Y., Gao, Z., Marks, P. A., and Jiang, X. (2004). Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA 101, 18030–18035.
Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C. B., and Tsujimoto, Y. (2004). Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol 6, 1221–1228.
Shintani, T., Mizushima, N., Ogawa, Y., Matsuura, A., Noda, T., and Ohsumi, Y. (1999). Apg10p, a novel protein-conjugating enzyme essential for autophagy in yeast. EMBO J 18, 5234–5241.
Stack, J. H., DeWald, D. B., Takegawa, K., and Emr, S. D. (1995). Vesicle-mediated protein transport: regulatory interactions between the Vps15 protein kinase and the Vps34 PtdIns 3-kinase essential for protein sorting to the vacuole in yeast. J Cell Biol 129, 321–334.
Sugimoto, M., Kuo, M. L., Roussel, M. F., and Sherr, C. J. (2003). Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing. Mol Cell 11, 415–424.
Suzuki, K., Kirisako, T., Kamada, Y., Mizushima, N., Noda, T., and Ohsumi, Y. (2001). The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 20, 5971–5981.
Takeuchi, H., Kondo, Y., Fujiwara, K., Kanzawa, T., Aoki, H., Mills, G. B., and Kondo, S. (2005a). Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 65, 3336–3346.
Takeuchi, H., Kanzawa, T., Kondo, Y., and Kondo, S. (2005b). Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells. Br J Cancer 90, 1069–1075.
Tanida, I., Mizushima, N., Kiyooka, M., Ohsumi, M., Ueno, T., Ohsumi, Y., and Kominami, E. (1999). Apg7p/Cvt2p: A novel protein-activating enzyme essential for autophagy. Mol Biol Cell 10, 1367–1379.
Thumm, M., Egner, R., Koch, B., Schlumpberger, M., Straub, M., Veenhuis, M., and Wolf, D. H. (1994). Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett 349, 275–280.
Tian, J. H., Das, S., and Sheng, Z. H. (2003). Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18. J Biol Chem 278, 26265–26274.
Toth, S., Nagy, K., Palfia, Z., and Rez, G. (2002). Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res 309, 409–416.
Tsukada, M. and Ohsumi, Y. (1993). Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 333, 169–174.
Vande Velde, C., Cizeau, J., Dubik, D., Alimonti, J., Brown, T., Israels, S., Hakem, R., and Greenberg, A. H. (2000). BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20, 5454–5468.
Vetterkind, S., Illenberger, S., Kubicek, J., Boosen, M., Appel, S., Naim, H. Y., Scheidtmann, K. H., and Preuss, U. (2005). Binding of Par-4 to the actin cytoskeleton is essential for Par-4/Dlk-mediated apoptosis. Exp Cell Res 305, 392–408.
Wang, X., Li, W., Williams, M., Terada, N., Alessi, D. R., and Proud, C. G. (2001). Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 20, 4370–4379.
Webb, J. L., Ravikumar, B., and Rubinsztein, D. C. (2004). Microtubule disruption inhibits autophagosome-lysosome fusion: implications for studying the roles of aggresomes in polyglutamine diseases. Int J Biochem Cell Biol 36, 2541–2550.
Wishart, M. J., Taylor, G. S., and Dixon, J. E. (2001). Phoxy lipids: revealing PX domains as phosphoinositide binding modules. Cell 105, 817–820.
Xu, Y., Kim, S. O., Li, Y., and Han, J. (2006). Autophagy contributes to caspase-independent macrophage cell death. J Biol Chem 281, 19179–19187.
Xue, L., Fletcher, G. C., and Tolkovsky, A. M. (1999). Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci 114, 180–198.
Yan, C. H., Liang, Z. Q., Gu, Z. L., Yang, Y. P., Reid, P., and Qin, Z. H. (2006). Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. Toxicon 47, 521–530.
Yu, L., Alva, A., Su, H., Dutt, P., Freundt, E., Welsh, S., Baehrecke, E. H., and Lenardo, M. J. (2004). Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502.
Yu, L., Wan, F., Dutta, S., Welsh, S., Liu, Z., Freundt, E., Baehrecke, E. H., and Lenardo, M. (2006). Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA 103, 4952–4957.
Yue, Z., Jin, S., Yang, C., Levine, A. J., and Heintz, N. (2003). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 100, 15077–15082.
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Bialik, S., Kimchi, A. (2008). Autophagy and Tumor Suppression: Recent Advances in Understanding the Link between Autophagic Cell Death Pathways and Tumor Development. In: Programmed Cell Death in Cancer Progression and Therapy. Advances in Experimental Medicine and Biology, vol 615. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6554-5_9
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