p53Mdm2the affair that never ends
Dania Alarcon-Vargas and
Ze'ev Ronai,1
Ruttenberg Cancer Center Mount Sinai School of Medicine, New York, NY 10029, USA
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Abstract
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The p53Mdm2 paradigm represents the best-studied relationship between a tumor suppressor gene which functions as a transcription factor and an oncogene, which functions primarily as an E3 protein ligase. The intimate relationship between these two partners has expanded to include almost every cellular biological system from development, to growth control and programmed cell death. The affair between Mdm2 and p53 is closely controlled by a complex array of post-translational modifications, which in turn dictates the stability and activity of p53 and Mdm2. Functional diversity depends on the association with a large subset of partner proteins, which dictates the type of activity and corresponding selectivity. Here we summarize the current understanding of post-translational modifications and their effect on conformation-based functional relationship between Mdm2 and p53, as it pertains to their diverse cellular biological functions.
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p53
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The p53 tumor suppressor, is a nuclear phosphoprotein that functions as a DNA damage-inducible sequence specific transcription factor, as reviewed in refs18. In the absence of genetic damage, p53 transcriptional activity is inert (9), and is activated through signalling pathways that induce phosphorylation of the p53 protein in response to stress (reviewed in refs 1013). p53 has the typical structural domains of a transcription factor, which are supplemented by a proline-rich signalling domain (aa6194) and a regulatory domain (aa363393) (14). Depending on the conditions of cell growth, the type and duration of stress or DNA damage, p53 selectively activates a different subset of target genes which can cause either apoptosis, growth arrest, altered DNA repair, or altered differentiation (refs 15,16; Figure 1
). p53 regulates the G1-S checkpoint in response to relatively low doses of DNA damage, heat shock, hyperoxia, hypoxia and other forms of stress. Among the multiple targets for the transcriptionally active p53 which mediates efficient G1 arrest are cyclin-dependent kinase inhibitor p21WAF-1, 14-3-3, and reprimo, which enable a sufficient pause to allow for the repair of damaged DNA to take place (1719). Under extreme stress and severe DNA damage, p53 triggers the activation of genes implicated in the apoptotic cascade, including bax, DR5, p53AIP, PIDD, NOXA, PUMA, Fas/APO-1 and redox related genes (2023). The mechanisms that enable p53 to selectively trigger one of the two distinct pathways are the subject of intense investigations (24). The ability of p53 to exert regulation of such a large subset of genes can be attributed to its selective association with different transcription factors, each of which results in distinct regulatory output. Post-translational modifications are an important determinant in the association and transcriptional output of p53 by altering its conformation and concomitant association with other transcription factors and regulatory proteins (2426).
Over 18 phosphoacceptor sites were reported for p53. Most of them are modified in response to damage or stress (2741), although, several sites are phosphorylated under normal growth conditions (4245). It is the complexity of the phosphorylation on multiple sites that appears to dictate the fate and function of the protein. Phosphorylation of p53 differs during cell cycle progression in normal growing cells, and coincides with the ability of p53 to associate with some of its regulatory proteins including p300, Mdm2, and JNK (34,46). In vivo labeling of p53 revealed multiple forms of the protein, indicative of its diverse and complex phosphorylation. While phosphorylated on aa9 during G0, p53 is phosphorylated on residues 9, 15, 20, 372 during G1 and on aa37 and 392 during G2/M phase (34). The pattern of phosphorylation is altered significantly in response to stress and DNA damage (2742).
The complex phosphorylation of p53 is mediated by multiple kinases. In many cases, more than one kinase demonstrated the ability to phosphorylate the same phosphoacceptor residue. Figure 2
summarizes the current knowledge of p53 phosphorylation and the corresponding kinases implicated in this phosphorylation. Since signaling cascades often exhibit active cross-talk, it is possible to understand the nature of the cross reactivity reported to date. Among the better-characterized studies regarding the role of a given kinase in selective phosphorylation and function of p53 are those that relied on the use of knockouts, either by constitutive down regulation or, conversely, activation of the respective kinase. Along those lines, ATM and ATR were confirmed as kinases that contribute to p53 phosphorylation on serine 15 (27,28), and Chk2 is among the kinases that contribute to phosphorylation of p53 on serine 20 and possibly other sites (32,33). Both sites were shown to play an important role in the ability of p53 to associate with Mdm2, and in conferring p53 stability and transcriptional activities (47). JNK phosphorylation of p53 on Thr81 represents the recent addition of a site that appears to play an important role in p53 stability and transcriptional activities (48).

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Fig. 2. Currently known phospho-acceptor sites on p53 and the corresponding kinases implicated in their phosphorylation is illustrated.
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The diverse sites and motifs that are phosphorylated require that multiple phosphatases will be engaged in the regulation of p53 phosphorylation. The corresponding phosphatases are yet to be identified and characterized, but are expected to play a key role in the regulation of p53 stability and activities (49). Phosphatases are likely to regulate p53 following stress, as revealed from dephosphorylation of Ser376 within 30 min after exposure to ionizing irradiation (40).
The pattern of p53 phosphorylation is altered in human tumors, which exhibit a substantially greater degree of overall phosphorylation, independent of tumor type, or the form (wild type or mutant p53), which points towards a more general failure of one or more of the p53 phosphatases (50). Extensive phosphorylation, in contrast to what is seen in untransformed cells, is expected to alter the conformation of p53 and its corresponding association with other transcription factors, thereby providing a mechanism by which p53 activities can be altered in human tumors that do not harbor mutant forms of p53 (51). The latter may explain the increasing evidence for malfunction of p53, despite its wt form in human tumors (52). Of interest to note is that a recently reported NMR-based analysis rules out the allosteric model for the regulation of p53 (53).
In addition to its complex pattern of phosphorylation, p53 is acetylated on at least 3 known residues, aa320, 373 and 382. p53 acetylation is mediated by pCAF and CBP/p300 in response to DNA damage and stress, and is possibly dependent on its phosphorylation. Acetylation has been implicated in transcriptional activities of p53 and its association with members of the basal transcriptional machinery (5457). The finding that DNA damage inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53 highlights one mechanism that underlies the regulation of p53 acetylation (58).
In addition, p53 was shown to undergo conjugation to a small ubiquitin like protein named SUMO. Although originally implicated in its sub-nuclear localization and possible transcriptional activities (5961), a recent study rules out these functions (62). Furthermore, the relatively low level of sumoylated p53, which is not affected in response to stress or DNA damage suggests that p53 in its sumoylated form may acquire other cellular functions, yet to be identified. p53 sumoylation is facilitated by the activity of PIASI, which is implicated as a Sumo ligase towards p53 (63).
About 50% of many human tumor types carry a p53 mutation. Most of the mutations are localized within the DNA binding domain, thereby affecting p53 transcriptional activities. Such mutations can partially or completely abrogate the ability of p53 to elicit transcriptional activities (6466). As a result, the ability of p53 to elicit growth arrest, apoptosis, or both, is impaired. Some mutations were reported to render p53 transcriptionally active towards a new subset of genes, which results in gain of function phenotypes (67,68). Characteristic of mutant p53 is its elevated expression due to greater stability, which is attributed to its inability to induce the expression of its primary regulator, Mdm2 (69).
The growing number of proteins implicated in the regulation of p53 stability can be divided into targeting and protecting molecules. Among proteins that protect p53 from degradation are HIF1
, WT1, p300, TAFII31, and the viral proteins, SV40, large T antigen, and E1B (7075). It is the balance between stabilizing and degrading molecules that eventually dictates the outcome of p53 stability. This balance is likely to be affected by the conformation of p53, which is modified upon its phosphorylation or mutation, thereby altering the affinity for association with a select set of proteins (76). Cell cycle, stress, and DNA damage, are among the most well characterized scenarios known to involve altered p53 phosphorylation and the subsequent change in its association with targeting or stabilizing molecules (Figure 3
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Fig. 3. Outlined are proteins implicated in the stabilization (right) versus the degradation of p53 (left).
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Mdm2
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The mdm2 gene is a cellular proto-oncogene that is often amplified in
7% of all human cancers, but is more frequently observed in soft-tissue sarcomas (7779). Over-expression of MDM2 protein can also occur by increased transcription or enhanced translation (80). In combination with a p53 mutation, the prognosis is worse than either event alone (81,82). Experiments with knock-out mice revealed that deletion of the mdm2 gene results in embryonic lethality, which can be rescued by the deletion of the p53 gene (83,84). Inhibition of cell growth and marked cell death are often seen in the absence of p53 regulation by MDM2, further emphasizing the importance of the p53Mdm2 auto-regulatory loop in the control of cell growth and death. MDM2 protein regulates the activity of p53 protein by blocking its transcriptional activity, exporting of p53 protein into the cytoplasm, and/or by promoting the degradation of the p53 protein.
MDM2 possesses activities of a ubiquitin ligase, capable of self-ubiquitination (85,86), as well as targeted ubiquitination of its substrates, among which is p53 (8790). The E3 activity of MDM2 is centered within the RING finger domain (86). The balance between self- and targeted-ubiquitination of Mdm2 is modulated by its post translational modifications, including phosphorylation and sumoylation. Upon Sumo conjugation to Mdm2, its E3 ligase activities are shifted towards p53, while its self-ubiquitination is minimized. DNA damage and stress reduce Mdm2 sumoylation, which renders more of Mdm2 subject to self-ubiquitination and degradation. Consequently, the degree of p53 ubiquitination decreases and the amount of p53 readily available for mediating its transcriptional activities increases (91,92). Marking p53 for degradation is only one part of MDM2's role in promoting degradation. The MDM2 protein contains nuclear localization and nuclear export signals within its structure (93), and as a result MDM2 constantly shuttles between the nucleus and the cytoplasm. The p53 protein also contains its own export signals, located within the amino and carboxy terminal regions (94). The Mdm2 protein, through binding p53 protein, shuttles p53 protein out of the nucleus, into the cytoplasm where it is degraded (95). Nuclear export of p53 independent of Mdm2 was also shown to exist (96). Entry of Mdm2 into the nucleus was recently shown to be dependent on its phosphorylation by the PI3K/AKT kinases (97).
The ability of Mdm2 to associate with, and target, p53 degradation highly depends on the phosphorylation status of p53, as well as on the association of p53 with other cellular proteins. For example, Mdm2 binding can be outcompeted by a member of the basal transcriptional machinery, TAFII31, which associates with p53 in the same region as that utilized by Mdm2 for binding, within the amino terminal domain of p53 (73). In response to stress and damage, when p53 phosphorylation takes place on multiple residues, including those spanning the Mdm2 binding sites, Mdm2 no longer associates with p53 (47,90).
Whereas Mdm2 is a major regulator of p53 stability, other proteins are implicated in the regulation of p53 stability including JNK (46), human papilloma virus E6 (98), and COP9 signalosome complex (45). Of interest to note is that all non-Mdm2 regulators require the proline rich domain of p53 for the ability to affect p53 stability. The JNK association site (aa97106) was also found to be important in JAB1 and E6 association (45,99). Phosphorylation of p53 by JNK, which stabilizes p53 and enables it to be transcriptionally active, is mapped to T81, which is found within the proline rich domain required for non-Mdm2 based regulation of p53 stability (48).
Mdm2 phosphorylation is an emerging area of development subject to growing complexity (100). To date, the kinases implicated in Mdm2 phosphorylation and function are DNA-PK, ATM, AKT, p38, and Cdk (refs 97,101104; Z.Ranai, unpublished data). The finding that the same kinase can phosphorylate both Mdm2 and p53 further adds to the closely connected regulation between the two proteins. Whereas p38 was found to phosphorylate p53 at least on two residues, resulting in its greater stability (105,106), phosphorylation of Mdm2 results in reduction of its stability due to its increased self-ubiquitination, rendering less Mdm2 available for targeting the degradation of p53. Phosphorylation by ATM causes p53 stability due to interference with Mdm2 association (27,28), whereas ATM phosphorylation of Mdm2 affects its nuclear export (103). AKT phosphorylation of Mdm2 was demonstrated to be required for its nuclear import, an essential step that allows Mdm2 access to the cellular compartment in which it affects p53 activity and stability (97).
In addition to regulation by phosphorylation, various Mdm2 forms are products of alternate splicing or caspase cleavage (107,108). Each of these forms renders Mdm2 inactive, either due to loss of the amino terminal domain that is required for association with p53, or due to deletion of the RING domain, which is required for its activity as an E3 ligase. Truncated forms of Mdm2 efficiently inhibit the activity of full-length Mdm2, thereby serving to inhibit Mdm2 targeted ubiquitination and degradation of p53, resulting in elevated levels of p53 (109,110). Truncated forms of Mdm2 found in human tumors (111) further support the notion that Mdm2 may play a role in tumorigenesis, independent of p53. Along these lines, one would expect that Mdm2 would regulate proteins independent of p53. Indeed, recent studies highlight proteins that are affected by Mdm2, including Numb (112), MTBP (113) and ß2-adrenergic receptor and its regulatory protein ß-arrestin (114). A novel pathway for Mdm2 targeted ubiquitination was recently demonstrated through its effects on glucocorticoid receptors (GR), where the ability of Mdm2 to alter GR stability was found to be p53-dependent (115). One would expect additional proteins to be targets for Mdm2 via p53, a pathway that offers a novel layer in the regulation of p53-associated proteins and the function of p53 as well.
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The interplay between p53 and Mdm2
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A growing number of proteins are implicated in the regulation of both p53 and Mdm2 (Figure 4
). These include p300, E2F1, and at least 3 kinases, p38, CK1 and ATM (116119). Of interest is the reciprocal effect of ATM and p38 on Mdm2 versus p53. While phosphorylation of MDM2 inhibits its activities due to increased self-ubiquitination and altered cellular localization, both kinases increase p53 stability and limit the association of p53 with Mdm2. Figure 4
outlines the genes that are common as well as those that are distinct p53 and Mdm2 effectors. Under normal growth conditions, Mdm2 effectively targets, in concert with JNK and COP9, the degradation of p53. PKB signaling appears to increase Mdm2 targeting of p53 via alteration of Mdm2 localization and E3 ligase activities (97). Important components that affect this auto-regulatory feedback loop include the tumor suppressor protein, p14ARF (p19ARF in mice) (120,121). The p14ARF protein has a tumor suppressor function that relies on wild type p53 function. The p14ARF protein binds MDM2 protein, and inhibits the E3 activity of MDM2 (122), in addition to sequestering MDM2 into the nucleolus (123,124). Consequently, p14ARF disrupts the negative feedback inhibition of p53 by the binding to MDM2 (125,126). Somewhat similar to the effect of p14 is that of MDMx (Mdm4), a homologue of Mdm2 that associates with Mdm2 and attenuates its E3 ligase activities (Z.Ronai, unpublished data), and is capable of attenuating p53 transcriptional activities in vitro (127130). The importance of Mdm4 to cellular growth functions and possible tumorigenicity is best illustrated in the finding that Mdm4 knock out mice fail to develop, and can be rescued by crossing with p53 knock out mice, thereby resembling some of the major characteristics of Mdm2 (131).
ß-catenin was also shown to affect the Mdm2 p53 regulatory cascade in its ability to increase the amount of transcriptionally active p53 (132). This effect appears to be mediated at least in part through the ability of ß-catenin to increase the transcription of p19ARF which inactivates Mdm2 E3 ligase activity, thereby stabilizing the amount of p53 available to mediate its transcriptional output. In as much, the availability of wt p53 may serve to attenuate the oncogenic effects of ß-catenin. Furthermore, the ß-cateninp19-Mdm2-p53 cascade appears to cooperate with Ras mediated cellular transformation (133). Of interest is that while Ras is capable of inducing p19ARF expression (which would support the above pathway), it could also increase the levels of Mdm2, through increased Mdm2 transcription, thereby limiting availability of p53 (134). The mechanism that underlies the balance between the two pathways requires further investigation. Somewhat similar to the effect of ß-catenin is that of E2F1 which is also capable of increasing p19ARF expression, thereby limiting Mdm2 E3 ligase activities and enabling the accumulation of p53 (135). Mutations in Rb, or in ß-catenin, which are a common occurrence in human tumors, would therefore serve to further elevate the levels of p19ARF with consequent effects on Mdm2 and p53. Similarly, mutant forms of the Ras oncogene or over expression of c-myc would result in elevated E2F1 expression, thereby enabling an independent pathway for the up-regulation of p19ARF (135). Figure 5
outlines the components known to affect the complex interplay between p53 and Mdm2.

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Fig. 5. The interplay. p53 in its transcriptionally active form, which occurs in response to stress and DNA damage, is capable of activating distinct target genes that contribute to either apoptosis or growth arrest, as illustrated in each of the two blocks, respectively. Among the targets for p53 is Mdm2, which in turn serve to limit the amount of p53 via its efficient targeting of p53 degradation under non-stressed and normal growth conditions. p53 could activate PTEN which in turn inactivates AKT thereby inhibiting anti-apoptotic signals that are otherwise elicited from AKT. PKB phosphorylation of Mdm2 is required for Mdm2 entry to the nucleus, where it can exercise the regulation of p53 stability and activity, thereby resulting in p53 degradation. E2F1, normally regulated by Rb, is capable of increasing p14ARF expression levels, similar to the effects of ß-catenin. p14ARF in turn inhibits Mdm2 E3 ligase activities, via accelerated degradation of Mdm2, which require phosphorylation of Mdm2 by p38. Consequently, activation of p14ARF results in the stabilization of p53. Other factors that affect Mdm2 stability and activity include Raf/Ras signaling which could induce Mdm2 transcription, or p14ARF expression, thereby eliciting opposing signals towards Mdm2 and p53. Arrows colored in blue reflect transcriptional activation of downstream effector; red arrows reflect phosphorylation that acquires stability or activity; orange arrows represent degradation pathways.
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The affair that never endsepilogue
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The best evidence for the vital need for the regulation of the relationship between p53 and Mdm2 for cell development and proper protection from DNA damage and stress comes from genetic studies where the corresponding partners were deleted. Biochemical analysis adds more layers to the complexity of this affair, which includes almost every pathway involved in the control of cell cycle and growth. Charge and conformation appear to be the critical requirements for the regulation of the affair between p53 and Mdm2. The p53Mdm2 relationship is vital not only for essential functions of the cell, but it also appears to be an integrated part of the complex cellular network involving other signaling cascades, including Wnt (via ß-catenin), Ras, Rb, myc and more. The greater complexity supports the importance of this affair, which is a hallmark for its co-existence. This affair is also among the most intense targets for design and development of therapeutic strategies for cancer treatment (136,137).
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Notes
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1 To whom correspondence should be addressed Email: zeev.ronai{at}mssm.edu 
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Acknowledgments
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We apologize to the many authors of papers, which were not cited in this commentary due to space limitations. We thank members of the Ronai Lab for discussions and Curt Harris and Jim Manfredi for comments. Support by NCI grant CA78419 is gratefully acknowledged.
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Received November 21, 2001;
revised November 21, 2001;
accepted November 21, 2001.