The first reports that linked apoptosis with changes in ubiquitylation and proteasome composition and activities emerged from studies of intersegmental muscle programmed cell death in the hawkmoth Manduca sexta. Proteasome-inhibitor-based studies further corroborated the proposed link between the ubiquitin/proteasome system and apoptotic pathways.
By transactivating various apoptogenic substrates, but also through transcriptionally independent activities, p53 can activate the two important apoptotic pathways in cells. The function of p53 is substantially controlled through ubiquitylation by Mdm2, a RING-finger-dependent ubiquitin protein ligase for p53.
In addition to p53, many cell-cycle regulatory proteins, such as cyclins and CDK inhibitors, affect apoptotic pathways. Modulation of proteasomal proteolysis of these regulatory proteins often affects the execution of apoptosis.
NF-κB directs the transcription of several survival genes, although, under some circumstances, it can also promote apoptosis. The ubiquitin/proteasome system effectively governs NF-κB activation by aiding the post-translational processing of the NF-κB precursors and by controlling its nuclear localization.
The delicate balance between pro- and anti-apoptotic Bcl-2 family members within a cell helps determine the susceptibility of a cell to a death signal. Various Bcl-2 family members have been identified as substrates of the proteasome, and inhibition of their degradation has been found to affect apoptosis.
In response to apoptotic stimuli, the ubiquitin-ligase activity of IAPs (inhibitors of apoptosis) can lead to their auto-ubiquitylation and degradation, which allows cells to commit to apoptosis. Moreover, IAPs are also instrumental in modulating the amount of caspases through ubiquitylation leading to proteolysis, thereby irreversibly shutting down specific cell-death pathways.
Seeing through the multiple links between the ubiquitin/proteasome system and the apoptotic machinery is expected to significantly extend the repertoire of possible treatments to diseases that are linked to dysregulated cell death.
The ubiquitin/proteasome pathway is the main non-lysosomal route for intracellular protein degradation in eukaryotes. It is instrumental to various cellular processes, such as cell-cycle progression, transcription and antigen processing. Recent findings also substantiate a pivotal role of the ubiquitin/proteasome pathway in the regulation of apoptosis. Regulatory molecules that are involved in programmed cell death have been identified as substrates of the proteasome. Moreover, key regulators of apoptosis themselves seem to have an active part in the proteolytic inactivation of death executors.
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Meier, P., Finch, A. & Evan, G. Apoptosis in development. Nature 407, 796–801 (2000).
Krammer, P. H. CD95's deadly mission in the immune system. Nature 407, 789–795 (2000).
Rich, T., Allen, R. L. & Wyllie, A. H. Defying death after DNA damage. Nature 407, 777–783 (2000).
Hengartner, M. O. The biochemistry of apoptosis. Nature 407, 770–776 (2000).
Hacker, G. The morphology of apoptosis. Cell Tissue Res. 301, 5–17 (2000).
Adams, J. M. & Cory, S. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem. Sci. 26, 61–66 (2001).
Deveraux, Q. L. & Reed, J. C. IAP family proteins — suppressors of apoptosis. Genes Dev. 13, 239–252 (1999).
Jentsch, S. & Schlenker, S. Selective protein degradation: a journey's end within the proteasome. Cell 82, 881–884 (1995).
Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).
Weissman, A. M. Themes and variations on ubiquitylation. Nature Rev. Mol. Cell Biol. 2, 169–178 (2001).
Schwartz, L. M., Myer, A., Kosz, L., Engelstein, M. & Maier, C. Activation of polyubiquitin gene expression during developmentally programmed cell death. Neuron 5, 411–419 (1990).
Orlowski, R. Z. The role of the ubiquitin-proteasome pathway in apoptosis. Cell Death Differ. 6, 303–313 (1999).
Wojcik, C. Proteasomes in apoptosis: villains or guardians? Cell Mol. Life Sci. 56, 908–917 (1999).
Dawson, S. P. et al. Developmental changes of the 26S proteasome in abdominal intersegmental muscles of Manduca sexta during programmed cell death. J. Biol. Chem. 270, 1850–1858 (1995).
Jones, M. E., Haire, M. F., Kloetzel, P. M., Mykles, D. L. & Schwartz, L. M. Changes in the structure and function of the multicatalytic proteinase (proteasome) during programmed cell death in the intersegmental muscles of the hawkmoth, Dev Biol 169, 436–447 (1995).
Duan, H. et al. SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents. Mol. Cell Biol. 19, 3145–3155 (1999).
Lisztwan, J., Imbert, G., Wirbelauer, C., Gstaiger, M. & Krek, W. The von Hippel–Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev. 13, 1822–1833 (1999).
Pause, A. et al. The von Hippel–Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Natl Acad. Sci. USA 94, 2156–2161 (1997).
Gorospe, M. et al. Protective function of von Hippel–Lindau protein against impaired protein processing in renal carcinoma cells. Mol. Cell. Biol. 19, 1289–1300 (1999).
Schoenfeld, A. R. et al. The von Hippel–Lindau tumor suppressor gene protects cells from UV-mediated apoptosis. Oncogene 19, 5851–5857 (2000).
Devarajan, P. et al. The von Hippel–Lindau gene product inhibits renal cell apoptosis via Bcl-2-dependent pathways. J. Biol. Chem. 276, 40599–40605 (2001).
Raasi, S., Schmidtke, G. & Groettrup, M. The ubiquitin-like protein FAT10 forms covalent conjugates and induces apoptosis. J. Biol. Chem. 276, 35334–35343 (2001).
Takayama, S. et al. Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity. Cell 80, 279–284 (1995).
Mikula, M. et al. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J. 20, 1952–1962 (2001).
Jesenberger, V. et al. Protective role of Raf-1 in Salmonella-induced macrophage apoptosis. J. Exp. Med. 193, 353–364 (2001).
Wang, H. G., Takayama, S., Rapp, U. R. & Reed, J. C. Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. Proc. Natl Acad. Sci. USA 93, 7063–7068 (1996).
Matsuzawa, S., Takayama, S., Froesch, B. A., Zapata, J. M. & Reed, J. C. p53-inducible human homologue of Drosophila seven in absentia (Siah) inhibits cell growth: suppression by BAG-1. EMBO J. 17, 2736–2747 (1998).
Thress, K., Henzel, W., Shillinglaw, W. & Kornbluth, S. Scythe: a novel reaper-binding apoptotic regulator. EMBO J. 17, 6135–6143 (1998).
Thress, K., Evans, E. K. & Kornbluth, S. Reaper-induced dissociation of a Scythe-sequestered cytochrome c-releasing activity. EMBO J. 18, 5486–5493 (1999).
Shinohara, K. et al. Apoptosis induction resulting from proteasome inhibition. Biochem. J. 317, 385–388 (1996).
Drexler, H. C. Activation of the cell death program by inhibition of proteasome function. Proc. Natl Acad. Sci. USA 94, 855–860 (1997).
Grimm, L. M., Goldberg, A. L., Poirier, G. G., Schwartz, L. M. & Osborne, B. A. Proteasomes play an essential role in thymocyte apoptosis. EMBO J. 15, 3835–3844 (1996).
Sadoul, R. et al. Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons. EMBO J. 15, 3845–3852 (1996).
Grimm, L. M. & Osborne, B. A. Apoptosis and the proteasome. Results Probl. Cell Differ. 23, 209–228 (1999).
Miyashita, T., Harigai, M., Hanada, M. & Reed, J. C. Identification of a p53-dependent negative response element in the Bcl-2 gene. Cancer Res. 54, 3131–3135 (1994).
Sadot, E., Geiger, B., Oren, M. & Ben-Ze'ev, A. Down-regulation of β-Catenin by activated p53. Mol. Cell. Biol. 21, 6768–6781 (2001).
Amson, R. B. et al. Isolation of 10 differentially expressed cDNAs in p53-induced apoptosis: activation of the vertebrate homologue of the Drosophila seven in absentia gene. Proc. Natl Acad. Sci. USA 93, 3953–3957 (1996).
Wu, G. S. et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genet. 17, 141–143 (1997).
Muller, M. et al. p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med. 188, 2033–2045 (1998).
Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001).
Fortin, A. et al. APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J. Cell Biol. 155, 207–216 (2001).
Ryan, K. M., Phillips, A. C. & Vousden, K. H. Regulation and function of the p53 tumor suppressor protein. Curr. Opin. Cell Biol. 13, 332–337 (2001).References 35–42 report on key regulators of apoptosis as transcriptional targets of p53.
Marchenko, N. D., Zaika, A. & Moll, U. M. Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J. Biol. Chem. 275, 16202–16212 (2000).
Bennett, M. et al. Cell surface trafficking of Fas: a rapid mechanism of p53-mediated apoptosis. Science 282, 290–293 (1998).
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H. & Weissman, A. M. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 275, 8945–8951 (2000).
Haupt, Y., Maya, R., Kazaz, A. & Oren, M. Mdm2 promotes the rapid degradation of p53. Nature 387, 296–299 (1997).
Kubbutat, M. H., Jones, S. N. & Vousden, K. H. Regulation of p53 stability by Mdm2. Nature 387, 299–303 (1997).References 46 and 47 identify Mdm2-promoted degradation of p53 as a mechanism to ensure effective termination of the p53 signal.
Boyd, S. D., Tsai, K. Y. & Jacks, T. An intact HDM2 RING-finger domain is required for nuclear exclusion of p53. Nature Cell Biol. 2, 563–568 (2000).
Geyer, R. K., Yu, Z. K. & Maki, C. G. The MDM2 RING-finger domain is required to promote p53 nuclear export. Nature Cell Biol. 2, 569–573 (2000).
Hsieh, J. K. et al. RB regulates the stability and the apoptotic function of p53 via MDM2. Mol. Cell 3, 181–193 (1999).
Sharp, D. A., Kratowicz, S. A., Sank, M. J. & George, D. L. Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J. Biol. Chem. 274, 38189–38196 (1999).
Zhang, Y. & Xiong, Y. Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. Mol. Cell 3, 579–591 (1999).
Fuchs, S. Y. et al. JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes Dev. 12, 2658–2663 (1998).
Pagano, M. et al. Role of the ubiquitin–proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269, 682–685 (1995).
Vlach, J., Hennecke, S. & Amati, B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J. 16, 5334–5344 (1997).
Nakayama, K. et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J. 19, 2069–2081 (2000).
Roy, N., Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16, 6914–6925 (1997).
Deveraux, Q. L., Takahashi, R., Salvesen, G. S. & Reed, J. C. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388, 300–304 (1997).This study uncovers the function of IAPs as caspase inhibitors.
Deveraux, Q. L. et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223 (1998).
Hauser, H. P., Bardroff, M., Pyrowolakis, G. & Jentsch, S. A giant ubiquitin-conjugating enzyme related to IAP apoptosis inhibitors. J. Cell Biol. 141, 1415–1422 (1998).The identification of a ubiquitin-conjugating enzyme with a BIR domain.
Joazeiro, C. A. & Weissman, A. M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552 (2000).
Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M. & Ashwell, J. D. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288, 874–877 (2000).Report on the autoubiquitylation and degradation of IAPs as a key event in the apoptotic programme.
Huang, H. et al. The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. J. Biol. Chem. 275, 26661–26664 (2000).
Suzuki, Y., Nakabayashi, Y. & Takahashi, R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc. Natl Acad. Sci. USA 98, 8662–8667 (2001).The first study to provide evidence that an IAP can promote the degradation of an active caspase in living cells.
Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).
Palombella, V. J., Rando, O. J., Goldberg, A. L. & Maniatis, T. The ubiquitin–proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB. Cell 78, 773–785 (1994).This report provides evidence that the ubiquitin/proteasome pathway functions in the regulated processing of NF-κB precursors into active proteins.
Coux, O. & Goldberg, A. L. Enzymes catalyzing ubiquitination and proteolytic processing of the p105 precursor of nuclear factor κB1. J. Biol. Chem. 273, 8820–8828 (1998).
Hayashi, T. & Faustman, D. Essential role of human leukocyte antigen-encoded proteasome subunits in NF-κB activation and prevention of tumor necrosis factor-α-induced apoptosis. J. Biol. Chem. 275, 5238–5247 (2000).
Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000).By showing that IKK is activated through the assembly of Lys63-linked multiubiquitin chains, this study unveils a new regulatory function for ubiquitin in the activation of the NF-κB pathway.
Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).This study extends the finding that kinases can be activated by ubiquitylation.
Tanaka, M. et al. Embryonic lethality, liver degeneration, and impaired NF-κB activation in IKK-β-deficient mice. Immunity 10, 421–429 (1999).
Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V. & Baldwin, A. S. Jr. NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281, 1680–1683 (1998).
Wu, M. X., Ao, Z., Prasad, K. V., Wu, R. & Schlossman, S. F. IEX-1L, an apoptosis inhibitor involved in NF-κB-mediated cell survival. Science 281, 998–1001 (1998).
Zong, W. X., Edelstein, L. C., Chen, C., Bash, J. & Gelinas, C. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB that blocks TNFα-induced apoptosis. Genes Dev. 13, 382–387 (1999).
Kreuz, S., Siegmund, D., Scheurich, P. & Wajant, H. NF-κB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol. Cell. Biol. 21, 3964–3973 (2001).
Grossmann, M. et al. The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J. 19, 6351–6360 (2000).References 72–76 identify key regulators of apoptosis as gene targets of NF-κB transcriptional activity.
Tang, G. et al. Inhibition of JNK activation through NF-κB target genes. Nature 414, 313–317 (2001).
De Smaele, E. et al. Induction of Gadd45β by NF-κB downregulates pro-apoptotic JNK signalling. Nature 414, 308–313 (2001).
Barkett, M. & Gilmore, T. D. Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 18, 6910–6924 (1999).
Connolly, J. L. et al. Reovirus-induced apoptosis requires activation of transcription factor NF-κB. J. Virol. 74, 2981–2989 (2000).
Kasibhatla, S. et al. DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-κB and AP-1. Mol. Cell 1, 543–551 (1998).
Rivera-Walsh, I., Waterfield, M., Xiao, G., Fong, A. & Sun, S. C. NF-κB signaling pathway governs TRAIL gene expression and human T-cell leukemia virus-I tax-induced T-cell death. J. Biol. Chem. 276, 40385–40388 (2001).
Dimmeler, S., Breitschopf, K., Haendeler, J. & Zeiher, A. M. Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway. J. Exp. Med. 189, 1815–1822 (1999).
Breitschopf, K., Haendeler, J., Malchow, P., Zeiher, A. M. & Dimmeler, S. Posttranslational modification of Bcl-2 facilitates its proteasome-dependent degradation: molecular characterization of the involved signaling pathway. Mol. Cell. Biol. 20, 1886–1896 (2000).
Marshansky, V. et al. Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells. J. Immunol. 166, 3130–3142 (2001).
Breitschopf, K., Zeiher, A. M. & Dimmeler, S. Ubiquitin-mediated degradation of the proapoptotic active form of bid. A functional consequence on apoptosis induction. J. Biol. Chem. 275, 21648–21652 (2000).
Thomas, M. & Banks, L. Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene 17, 2943–2954 (1998).
Li, B. & Dou, Q. P. Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proc. Natl Acad. Sci. USA 97, 3850–3855 (2000).
Peter, M. E., Heufelder, A. E. & Hengartner, M. O. Advances in apoptosis research. Proc. Natl Acad. Sci. USA 94, 12736–12737 (1997).
Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature Genet. 25, 302–305 (2000).
Cummings, C. J. et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24, 879–892 (1999).
Saigoh, K. et al. Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nature Genet. 23, 47–51 (1999).
Yuan, J. & Yankner, B. A. Apoptosis in the nervous system. Nature 407, 802–809 (2000).
Huang, P. & Oliff, A. Signaling pathways in apoptosis as potential targets for cancer therapy. Trends Cell Biol. 11, 343–348 (2001).
Baldwin, A. S. Jr. Series introduction: the transcription factor NF-κB and human disease. J. Clin. Invest. 107, 3–6 (2001).
Bondeson, J., Foxwell, B., Brennan, F. & Feldmann, M. Defining therapeutic targets by using adenovirus: blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc. Natl Acad. Sci. USA 96, 5668–5673 (1999).
Wang, C. Y., Cusack, J. C. Jr, Liu, R. & Baldwin, A. S. Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB. Nature Med. 5, 412–417 (1999).
Perkins, N. D. The Rel/NF-κB family: friend and foe. Trends Biochem Sci. 25, 434–440 (2000).
Lee, D. H. & Goldberg, A. L. Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol. 8, 397–403 (1998).
Adams, J. et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 59, 2615–2622 (1999)
Mlynarczuk, I. et al. Augmented pro-apoptotic effects of TRAIL and proteasome inhibitor in human promonocytic leukemic U937 cells. Anticancer Res. 21, 1237–1240 (2001).
Milligan, S. A. & Nopajaroonsri, C. Inhibition of NF-κB with proteasome inhibitors enhances apoptosis in human lung adenocarcinoma cells in vitro. Anticancer Res. 21, 39–44 (2001).
Mitsiades, C. S. et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 98, 795–804 (2001).
Franco, A. V. et al. The role of NF-κB in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells. J. Immunol. 166, 5337–5345 (2001).
Shah, S. A. et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J. Cell Biochem. 82, 110–122 (2001).
Cusack, J. C. Jr et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-κB inhibition. Cancer Res. 61, 3535–3540 (2001).
Teicher, B. A., Ara, G., Herbst, R., Palombella, V. J. & Adams, J. The proteasome inhibitor PS-341 in cancer therapy. Clin. Cancer Res. 5, 2638–2645 (1999).
Cheng, E. H. et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8, 705–711 (2001).
Koegl, M. et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96, 635–644 (1999).
Our apologies to those whose work could only be cited indirectly owing to space limitations. V.J. is supported by a Marie-Curie fellowship, S.J. by the Max Planck Society, Deutsche Forschungsgemeinschaft, European TMR network and Fonds der chemischen Industrie.
This is defined by stereotypical changes such as chromatin condensation, phosphatidylserine exposure, cytoplasmic shrinkage, membrane blebbing and the formation of apoptotic bodies. In its most classical form, apoptosis invariably involves caspase activation.
A family of cysteine proteases that can be grouped into initiator and effector caspases. Caspase activation requires their proteolytic cleavage to liberate subunits that reconstitute an active caspase heterodimer.
- BCL-2 FAMILY
(B-cell lymphoma-2 family). These are proteins with a structural similarity to Bcl-2, the prototypical inhibitor of apoptosis. The Bcl-2 family comprises proteins that both block and enhance apoptosis.
(Inhibitor of apoptosis proteins). These are intrinsic cellular inhibitors of apoptosis and are defined by the presence of BIR motifs.
- 26S PROTEASOME
A large barrel-shaped multisubunit protease complex that selectively degrades multiubiquitylated proteins. It contains a 20S subunit, which carries the catalytic activity, and two regulatory 19S subunits.
A 76-amino-acid globular protein that is highly conserved throughout eukaryotes. Its covalent conjugation to other proteins is essential for the degradation of proteins.
- E2 UBIQUITIN-CONJUGATING ENZYME
An enzyme that accepts ubiquitin from a ubiquitin-activating enzyme (E1) and, usually together with a ubiquitin ligase (E3), transfers it to a substrate protein.
- ISOPEPTIDE LINKAGE
Any amino bond formed between a carboxyl group of one amino acid and an amino group of another, in which either group occupies a position other than α.
- SCF UBIQUITIN-LIGASE COMPLEX
A multisubunit E3 ubiquitin ligase, which is composed of Skp1, cullin-1 protein, F-box protein, and Rbx1/Roc-1 RING-finger protein. The F-box protein is the substrate-recruiting factor.
- CBCVHL COMPLEX
An SCF-related complex of elongin B, elongin C, cullin-2 and the RING-finger protein Rbx1/Roc-1. The substrate-recognizing subunit pVHL binds to the elongin B/C complex through a motif known as the Socs box. It is believed that the von Hippel–Lindau cancer syndrome is a direct consequence of a loss of cellular CBCVHL-mediated ubiquitylation activity.
- TUMOUR-NECROSIS FACTOR-α
(TNF-α) A prototypic member of a family of cytokines that interact with several receptors, among them receptors that are responsible for eliciting apoptosis.
- PROTEASOME INHIBITORS
These are classified into four groups: lactacystin and β-lactone derivates, vinyl sulfones, peptide aldehydes and peptide boronates. The aldehyde and boronate inhibitors are reversible and more amenable to clinical use.
- RING-FINGER PROTEINS
A family of proteins that are structurally defined by the presence of the zinc-binding RING-finger motif. The RING consensus sequence is: CX2CX(9–39)CX(1–3)HX(2–3)C/HX2CX(4–48)CX2C. The cysteines and histidines represent metal binding sites. The first, second, fifth and sixth of these bind one zinc ion and the third, fourth, seventh and eighth bind the second zinc ion. Many RING-finger proteins are ubiquitin ligases or subunits thereof.
- TNF-RECEPTOR FAMILY
Members of this family function as trimers and multimers of trimers, and can trigger proliferation, survival, differentiation or death. A subfamily that comprises the death receptors Fas/CD95 and TNF-R1, as well as some other members of this family, contains a cytoplasmic region — the death domain — which is essential for inducing apoptosis.
- E3 UBIQUITIN-LIGASE
An enzyme that covalently attaches ubiquitin to a substrate protein in conjunction with E1 and E2. E3s range from single polypeptide chains to large complexes in which substrate recognition and ubiquitin conjugation occur in distinct subunits. So far, every known E3 has either a homologous to E6AP carboxyl-terminus (HECT) domain, or a RING-finger domain.
The c-Jun amino-terminal kinase belongs to the group of mitogen-activated protein kinases (MAPKs) and is activated in mammalian cells by environmental stress, pro-inflammatory cytokines and mitogenic stimuli. JNK regulates the activities of many transcription factors, and is required for the regulation of inflammatory responses, cell proliferation and apoptosis.
These function as positive regulatory subunits of cyclin-dependent kinases (CDKs). Cyclin–CDK complexes are usually activated at specific points during the cell cycle and have a specific set of substrates.
- CDK INHIBITORS
These inhibit cell-cycle progression by regulating cyclin–CDK complexes. On the basis of their structural and functional properties, CDK inhibitors fall primarily into the INK4 group and the Cip/Kip family.
- BIR MOTIF
A ∼70 amino-acid zinc-finger motif called the baculoviral inhibitor of apoptosis repeat. The number of BIR domains in a given IAP varies from one to three, but they are invariably present at the amino-terminus of the protein, and mediate the interaction with caspases.
- UBIQUITIN-CONJUGATING DOMAIN
(UBC). The ∼16-kDa ubiquitin-conjugating domain of E2s harbours the active-site cysteine residue that is required for the formation of a thioester-linked E2-ubiquitin complex.
(IKK). The 700–900-kDa IκB-kinase (IKK) complex includes the catalytic subunits IKKκ and IKKβ and the regulatory subunit IKKγ/NEMO. Both catalytic substrates are involved in the activation of NF-κB transcription factors, but they do so by distinct mechanisms and substrates. As shown by genetic studies, IKKβ is essential for inducible IκB phosphorylation and degradation.
- TNF-RECEPTOR-ASSOCIATED FACTORS
(TRAFs). These are adaptor proteins for various cell-surface receptors. Most TRAFs encode a RING-finger motif at their amino-terminus; in the case of TRAF2 and TRAF5, the RING-finger is required for NF-κB activation.
(TNF-related apoptosis-inducing ligand). This induces apoptosis preferentially in transformed cells. In contrast to other death-inducing ligands, TRAIL is expressed in a wide range of tissues.
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Jesenberger, V., Jentsch, S. Deadly encounter: ubiquitin meets apoptosis. Nat Rev Mol Cell Biol 3, 112–121 (2002). https://doi.org/10.1038/nrm731
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