Leukemia (2000) 14, 1509–1513  2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu REVIEW

Death and decoy receptors and p53-mediated MS Sheikh1 and AJ Fornace Jr2

1Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York; and 2Gene Response Section, Division of Basic Sciences, NCI, NIH, Bethesda, Maryland, USA

Recently, several 1 (TNF-R1) trimers and induce receptor trimerization; receptor trimeriz- and Fas-related death receptors have been discovered and ation is necessary for receptor activation (reviewed in Refs 1 include DR3, DR4, DR5 and DR6. These receptors contain an extracellular region containing varying numbers of cysteine- and 2). TNFR2 does not contain the intracellular death rich domains and an intracellular region that contains the and is generally not implicated in mediating the apop- domain. The death receptors are activated in a -depen- totic signals. Thus, TNF-R1 is the major receptor responsible dent or independent manner and transduce apoptotic signals for mediating the apoptotic signals of TNF ligand receptor sys- via their respective intracellular death domains. In addition to tem (Figure 1) (reviewed in Refs 1 and 2). TNF-R1 upon acti- death receptors, several decoy molecules have also been ident- vation recruits the intracellular adaptor molecule TRADD ified and include DcR1/TRID, DcR2/TRUNDD, DcR3 and osteo- (TNFR-associated death domain ). TRADD is a death protegrin (OPG). The decoy molecules do not transduce apop- 3 totic signals but rather compete with the death receptors for domain containing adaptor molecule that further recruits ligand binding and thereby inhibit ligand-induced apoptosis. another death domain containing protein FADD (Fas-associa- Recent evidence suggests that p53 upregulates the expression ted death domain protein).4,5 The interactions among these of death receptors Fas and DR5, and thus, may mediate adaptor molecules and TNF-R1 occur through their respective apoptosis in part via Fas and/or DR5. However, p53 also regu- death domains leaving free the N-terminal death effector lates the expression of TRAIL decoy receptors DcR1/TRID and DR2/TRUNDD. Although the significance of p53-dependent domain of FADD to further interact with the analogous regulation of decoy receptors remains unclear, evidence sug- domain of proximal procaspase 8 or 10 (Figure 1) (Refs 4 and gests that DcR1/TRUNDD appears to inhibit 53-mediated 5 and reviewed in Ref. 2). Recruitment of proximal procaspase apoptosis. It is, therefore, possible that p53 may blunt its DR5- at the receptor site results in its oligomerization-mediated acti- dependent apoptotic effects by controlling the levels of decoy vation (reviewed in Ref. 2). Once activated the proximal casp- receptors. Leukemia (2000) 14, 1509–1513. ases further activate the downstream such as Keywords: TNF-R superfamily; death domain 3, 6 and 7 also known as the executioner caspases (Figure 1). From the executioner caspases the apoptotic signal flows Introduction further downstream leading to cleavage of death substrates and eventually cell demise (Figure 1). Tumor necrosis factor receptor 1 (TNF-R1) and related ‘death In addition to activation of apoptotic axis, TNF-R1 also domain’ containing molecules form an emerging family of relays signals that impinge upon cell survival. For example, membrane death receptors that transduce apoptotic signals (reviewed in Refs 1 and 2). This family, named the TNF-R superfamily, contains six members including TNF-R1, Fas, DR3, DR4, DR5 and DR6. These receptors harbor an extra- cellular region with varying numbers of cysteine-rich domains and an intracellular region that contains ‘death domain’. The death domain is a stretch of amino acids that shows varying degree of homology among various death receptors and is critical for their apoptotic (reviewed in Ref. 2). The ligands for these receptors also form a family of related cytokines. Named the TNF family, it contains member cytokines such as TNF␣,LT␣, FasL, Apo3L and TRAIL (TNF- related apoptosis inducing ligand; also known as Apo2L) (reviewed in Ref. 2). These ligands function in an autocrine or paracrine manner to mediate their apoptotic effects via their respective cell surface membrane death receptors.

TNF␣ and TNF-R1 ligand/receptor complex

TNF␣ and another ligand LT␣ mediate their effects via TNF- R1 and TNFR2. These ligands bind to both receptors as homo-

Correspondence: MS Sheikh, Department of Pharmacology, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY 13210, USA; Fax: 315-464-9681 Received 6 March 2000; accepted 28 April 2000 Figure 1 TNF/TNF-R1-mediated apoptotic and survival pathways. Death and decoy receptors and p53 MS Sheikh and AJ Fornace Jr 1510 TRADD also recruits TRAF1 and TRAF2, the adaptor mol- ecules that lead to activation of JNK (Jun N-terminal kinase) and NF-␬B (Figure 1) (reviewed in Ref. 2). Recruitment of TRADD and FADD at the receptor site also promotes interac- tion with another death domain containing molecule RIP. Although less well studied, RIP has been shown to interact with RAIDD to activate caspase 2 in order to mediate apop- totic signals (Figure 1).6,7 More recently, a novel molecule named silencer of death domain (SODD) has been identified.8 SODD is believed to interact with the death domain of TNF- R1 and keeps the receptor in monomeric form.8 Upon acti- vation of TNF-R1, SODD dissociates form the receptor, the ensuing oligomerization of receptor results in its activation and consequently the apoptotic signals flow further down- stream.8 Thus, TNF-R1 activation involves complex series of interactions with the intracellular molecules to mediate apop- totic and survival signals. In general, transcription or synthesis inhibition potentiates TNF-induced apoptosis. Since TNF-R1 activation also results in concomitant activation of anti-apoptotic NF-␬B, it has been proposed that inhibition of NF-␬B-mediated effects by transcription and proteins synthesis inhibitors relieve from anti-apoptotic controls and the balance shifts in favor of apop- totic axis. Evidence in favor of this contention includes the NF-␬B-dependent upregulation of TRAF1, TRAF2, cIAP1 and cIAP2 expression.9 TRAFs have been shown to bind to TNF-R1 and prevent TNF␣-induced activation of at the receptor site while cIAPs inhibit caspase 3 and 7 acti- vation.9 TRAFs also serve to function in a positive feed back loop to further promote NF-␬B activation. Thus, transcription and proteins synthesis inhibitors appear to block NF-␬B- induced survival signals and consequently shift the balance in the favor of apoptotic signals.

FasL and receptor complex Figure 2 FasL/Fas-mediated apoptotic pathways. Upon activation, Fas directly recruits FADD and the procaspase 8 or 10 to mediate Fas, also known as CD95, is activated by its ligand FasL or apoptotic signals. Fas is also believed to mediate apoptosis via CD95L. Just like any other ligand in this family, FasL binds to Daxx/ASK1-dependent JNK activation. Fas as a homotrimer and activates its cognate receptor Fas (Figure 2) (reviewed in Refs 1 and 2). The basic paradigm of Fas activation is similar to that of TNF-R1 except that Fas does yet unidentified receptor(s) and/or functions predominantly in not interact with TRADD but directly recruits FADD (Figure 2) a paracrine manner. (reviewed in Refs 1 and 2). Fas also does not appear to interact with TRAFs and RAIDD (reviewed in Ref. 10). Although Fas- dependent activation of NF-␬B has been reported (reviewed in Ref. 10), Fas-mediated activation of NF-␬B remains less well TRAIL and DR4/DR5 ligand receptor complex established. Unlike TNF-R1, Fas has been shown to interact with a molecule named Daxx.11 Evidence suggests that Daxx As the name indicates, DR4 and DR5 are the fourth and fifth bridges Fas interactions with ASK1 (also known as MAP3 members of TNFR superfamily. Both DR4 and DR5 have been kinase) which results in subsequent activation of JNK pathway identified only recently and bind to their physiological ligand (Figure 2).12 Fas activation of JNK via Daxx and ASK1 is TRAIL (reviewed in Refs 2 and 16). Evidence suggests that believed to be a second pathway via which Fas mediates its both DR4 and DR5 appear to mediate their apoptotic signals apoptotic signals (Figure 2). in a manner similar to other family members but the adaptor molecule(s) that bridge their interactions with the intracellular proximal caspases has/have not been identified (reviewed in Apo3L and DR3 ligand receptor complex Refs 2 and 16). There has been some controversy regarding FADD being a molecule that bridges their interactions with DR3 is a third member of TNFR family and is activated by the proximal caspases. The controversy may stem from differ- its ligand Apo3L.13–15 DR3 is identical to TNF-R1 in terms of ences in the experimental systems used by different investi- interactions with intracellular molecules, however, unlike gators. However, cells from FADD-deficient animals were TNF-R1, DR3 expression is restricted to lymphocyte-rich proficient in DR4-mediated apoptosis17 suggesting that FADD tissues.13,14 It is interesting that Apo3L has a broader tissue may not be essential for the apoptotic effects of these death distribution than its cognate receptor DR3.13–15 This finding receptors. Evidence suggests that both of these receptors can raises the possibility that Aop3L may also bind to other as of also activate NF-␬B and JNK pathways.18,19

Leukemia Death and decoy receptors and p53 MS Sheikh and AJ Fornace Jr 1511 DR6 stress in a p53-dependent manner in some systems.36,43 Further studies are needed to determine whether FASL is a The sixth member in the TNFR family, DR6, is unusual in that direct target of p53. It is possible that p53-mediated upregul- it contains a eucine-zipper-like motif in its cytoplasmic ation of Fas and DR5 may engage the intracellular caspase region.20 The leucine-zipper-like motif overlaps with a pro- cascade to induce apoptosis (Figure 3). Although p53 may not line-rich motif that is believed to interact with src-homology- regulate DR5 ligand TRAIL, it may either induce both FasL 3 (SH3) domains. Although the ligand for DR6 has not been and Fas or only Fas to activate the apoptotic signals emanating identified, its overexpression has been shown to induce from this death receptor (Figure 3). A recent study has demon- apoptosis and activation of NF-␬B and JNK pathways.20 Avail- strated that p53 appears also to activate Fas by increasing the able evidence suggests that DR6 appears to mediate apoptosis translocation of Fas through Golgi to the cell surface.44 Evi- in a TRADD-dependent but FADD-independent manner.20 dence, however, suggests that p53 may not absolutely require The issue as to how DR6 talks to proximal caspases and the the FasL/Fas system to mediate its apoptotic effects.45,46 downstream caspase cascade remains unclear and requires In the case of DR5, p53 does not seem to regulate the further investigation. expression of its ligand TRAIL. However, overexpression of DR5 has been shown to induce apoptosis in a ligand-inde- pendent manner. It is therefore possible that p53 by upregulat- Decoy members of the TNFR family ing the levels of DR5 may activate DR5 in a ligand-inde- pendent manner (Figure 3). The requirement of DR5 during In addition to death receptors, four decoy molecules that p53-mediated apoptosis remains unclear. Given the multifa- belong to the TNFR family have also been identified. DcR1 ceted nature of p53-mediated apoptotic effects, p53 may not (also known as TRID or TRAIL-R3)21–23 and DcR2 (also known display an absolute requirement for DR5. Nevertheless, the as TRUNDD or TRAIL-R4)24–26 are cell surface proteins generation of DR5-deficient mice and cells might help in whereas DcR327 and OPG (osteoprotegrin)28 are soluble mol- addressing some of these issues. ecules. Both DcR1/TRID and DcR2/TRUNDD bind to TRAIL p53 has also been shown to induce the expression of with a similar affinity, as do DR4 and DR5. DcR1/TRID is DcR1/TRID41,42 and DCR2/TRUNDD.42 However, it is not a GPI (glycosylphosphatidylinositol)-linked protein devoid of clear whether p53 directly upregulates the expression of these intracellular death domain whereas DcR2/TRUNDD is a trans- . Furthermore, the significance of their upregulation by membrane receptor with a partially deleted death domain and p53 also remains unclear. p53-mediated induction of these accordingly, both are unable to transduce apoptotic signals genes occurs prior to (within 6 h) p53-induced growth arrest (reviewed in Refs 2 and 16). OPG is a secreted protein that or apoptosis suggesting that DcR1/TRID and DcR2/TRUNDD also binds to TRAIL but with much less affinity than the other upregulation is not the consequence of p53-induced growth receptors.28 DcR3 is closely related to OPG and like OPG, arrest.4,42 DcR2/TRUNDD overexpression has recently been DcR3 is also a secreted protein. DcR3 binds to Fas in a man- shown to partially protect from p53 and DR5-mediated ner similar to FasL and thus, blocks FasL/Fas-mediated apoptosis.42 The intracellular domain of DcR2/TRUNDD apoptosis.27

Death and decoy receptor regulation during p53-mediated apoptosis p53 is one of the most frequently mutated tumor suppressor genes. Abnormalities in p53 have been implicated in a variety of human cancers. The p53 protein is believed to play roles in various different cellular processes but is most extensively studied for its roles in growth arrest and apoptosis (reviewed in Refs 29–33). Despite the fact that p53 has been known for a long time and the fact that its role in apoptosis is undisputed, the exact mechanism(s) via which p53 mediates apoptosis remain less well understood. p53 functions as a transcription factor to modulate the expression of its downstream effector genes (reviewed in Refs 29–33). p53 transcriptionally induces the expression of a var- iety of genes whose products are believed to control apoptosis (reviewed in Refs 31 and 33). Evidence suggests that p53 also appears to induce apoptosis in a transcription-independent manner (Refs 34 and 35 and reviewed in Refs 29, 31 and 33). Transcription-dependent and -independent apoptotic func- tions of p53 may vary with the cell type and apoptotic insult. Recent studies suggest that the TNF ligand/receptor family members may also contribute to p53-mediated apoptotic sig- naling pathways. p53 has been shown to induce the expression of FAS,36–38 FASL,36 DR5,39,40 DcR1/TRID41 and Figure 3 p53 regulation of death and decoy receptor expression 42 may modulate p53-induced apoptosis. p53 may engage the casapase DcR2/TRUNDD. p53 appears to transcriptionally upregulate cascade via death receptors Fas and/or DR5. By upregulating the lev- the expression of FAS and DR5 (reviewed in Refs 30 and 31). els of decoy receptors DcR1/TRID and/or DcR2/TRUNDD, p53 may Evidence suggests that FASL is also regulated by genotoxic blunt its DR5-dependent apoptosis.

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