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Living with p53, Dying of p53

Living with p53, Dying of p53

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Published by Sebastian Estay
Yael Aylon1 and Moshe Oren1,*
Yael Aylon1 and Moshe Oren1,*

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Categories:Types, Research, Science
Published by: Sebastian Estay on Nov 18, 2010
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Leading Edge
Minireview
Cell
130
, August 24, 2007 ©2007 Elsevier Inc.
597
Cells are incessantly bombarded by an assortment o envi-ronmental and intrinsic actors that cause cellular damage. Although mild damage is oten reparable, extensive dam-age poses a potential oncogenic danger. In the latter case,the benet o the organism calls or the eradication o thepotentially lie-threatening cells, which oten is achievedthrough activation o an apoptotic cell death program.Thus, the cell is continually aced with an agonizing choice:repair and live, or die. Deects in this decision processcan lead to cancer, and insights into the mechanisms odysregulation can improve strategies or designing moreeective therapies. This cell ate choice oten dependson the tumor suppressor protein p53. Sitting at the junc-tion o an extremely complex network o cellular signaling,p53 assimilates disparate input signals such as oncogeneactivation, DNA damage, mitotic impairment or oxidativestress to initiate appropriate outputs—DNA repair, cellcycle arrest, senescence, or apoptosis (Harris and Levine,2005). This begs the question o how one molecule is ableto mediate such a wide spectrum o responses.Even though p53 can also unction in a transcrip-tion-independent manner (Fuster et al., 2007), the bestunderstood unctions o p53 have been attributed to itstranscriptional activity. In act, approximately hal o allcancers bear p53 gene mutations, the vast majority owhich impair the ability o p53 to act as a sequence-specic transcriptional activator. This underscores theimportance o p53-regulated genes or p53’s tumor sup-pressor activity.How p53 “knows” which genes to turn on or o inorder to achieve the desirable outcome has been aocus o intensive research (Harris and Levine, 2005;Laptenko and Prives, 2006). Particular eort has beendevoted to understanding how p53 is instructed to avoractivation o growth-inhibitory genes in response to lim-ited damage that calls or a transient cell cycle arrest inconjunction with repair, and activation o proapoptoticgenes in response to extensive irreparable damage. Twoexciting reports (Das et al., 2007; Tanaka et al., 2007) inthis issue describe two new partners or p53—the zincnger protein Hz and the chromatin-associated proteinCAS/CSE1L—that are involved in opposite arms o thep53 response.
Basic Rules o p53-DNA Binding
Sequence-specic DNA binding o p53 is a prerequisiteor the transactivation o target genes. Typically, p53response elements (p53REs) are located within a ewthousand nucleotides upstream or downstream rom thetranscription start site. Frequently, p53 targets containat least two widely spaced p53REs. However, not alltarget genes are equally responsive to p53, suggestingadditional layers o regulation.DNA topology o p53REs may serve as one struc-tural determinant infuencing promoter discrimination.The act that regions proximal to some p53REs (orexample, those o the
GADD45
and
Mdm2
genes) existconstitutively in open, non-nucleosome occupied stateswhereas others do not, might contribute to dierentialactivation o p53 target genes (Braastad et al., 2003).Furthermore, conormation o the DNA may be impor-tant. The recognition o elements in the
Mdm2
and
 p21
 promoters is dependent on their dierential propensitiesto adopt non-B-DNA conormations (Kim and Deppert,2003). More generally, the binding anities o p53 orspecic p53REs dier widely; high anity sites tend toassociate with growth arrest-related genes, whereas lowanity sites are more requent in proapoptotic genes(Inga et al., 2002).The dierent anities o p53 toward dierent p53REssuggest that levels o p53 protein may prooundly aectpromoter choice and cell ate. Indeed, low p53 levelstend to avor growth arrest, whereas higher levels over-ride this deault pathway and trigger apoptosis (Lap-tenko and Prives, 2006). This might explain, at least inpart, why binding to proapoptotic promoters, such as
PIG3
, is markedly delayed relative to binding to cell cyclearrest promoters such as
 p21
(Szak et al., 2001).
p53 Binding Proteins and the TranscriptionalResponse
Not surprisingly, the interaction between p53 and its DNAtarget sequences is highly infuenced by the cellular con-text. A plethora o partner proteins have been implicated inmodulating the selection o p53 targets (Figure 1). Some othose proteins are transcription actors themselves, whichpresumably bind to promoter sites adjacent to p53REs to
Livig with p53, Dyig of p53
 Yael Aylon
1
and Moshe Oren
1,
*
1
Department o Molecular Cell Biology, The Weizmann Institute o Science, Rehovot 76100, Israel*Correspondence.moshe.oren@weizmann.ac.ilDOI 10.1016/j.cell.2007.08.005
The p53 tumor suppressor protein acts as a major defense against cancer. Among its mostdistinctive features is the ability to elicit both apoptotic death and cell cycle arrest. Inthis issue of
Cell 
, Das et al. (2007) and Tanaka et al. (2007) provide new insights into themechanisms that dictate the life and death decisions of p53.
 
598
Cell
130
, August 24, 2007 ©2007 Elsevier Inc.
selectively induce specic response genes. Others infu-ence the ability o p53 itsel to bind preerentially to par-ticular DNA target sequences and not to others. The cellu-lar environment as well as the relative abundance o thesepotential partners under dierent conditions could obvi-ously tip the lie-or-death balance o p53 activity. ASPP amily proteins comprise three members: ASPP1, ASPP2 and inhibitory ASPP (iASPP) (Sullivanand Lu, 2007). Upon DNA damage, ASPP1 and 2 areactivated and then interact with the DNA binding domain(DBD) o p53, enhancing its tumor suppressor activity.Specically, they enhance p53’s apoptotic capabilitiesby guiding p53 to the promoters o proapoptotic genes,such as
Bax
and
PIG3
, but not to the promoters o pro-arrest genes such as
 p21
or regulatory genes such as
Mdm2
. In accordance with their potential tumor sup-pressor activity, ASPP1 and 2 are requently downregu-lated in human tumors (Sullivan and Lu, 2007). In con-trast iASPP, which counters the eects o ASPP1 and 2and intereres with activation o proapoptotic genes, isoten overexpressed in human tumors.The Brn3 amily o POU domain transcription actorsalso modulates p53 target selectivity. Whereas Brn3baugments the activation o proapoptotic genes, suchas
Bax
(Budhram-Mahadeo et al., 2006), Brn3a has theopposite eect. Brn3a and p53 directly interact dur-ing neuronal dierentiation to mutually modulate theirrespective transcriptional outputs. In that role, Brn3adiminishes the ability o p53 to transactivate the
Bax
pro-moter, while stimulating transcription o
 p21
, resulting ina net outcome o cell cycle arrest rather than apoptosis.YB1 is a DNA binding protein overexpressed in manytumor types. Stress signals trigger proteolytic cleavage oYB1 and p53-dependent nuclear import at the G1/S stageo the cell cycle. Once in the nucleus, the N-terminal rag-ment o YB1 directly binds to p53 to prevent transactiva-tion o proapoptotic genes (Homer et al., 2005).The transcription actor NF-
κ
B is also an importantmodulator o p53 transcriptional activity. While otenantagonizing p53 unction, NF-
κ
B can also sometimescooperate with p53. NF-
κ
B negatively aects p53 proteinlevels via positive regulation o Mdm2 expression. Com-petition or coactivators, such as p300 and CBP, mightprovide additional means or mutual negative regulation.Recent data indicate that phosphorylation o CBP byIKK
α
, which occurs excessively in certain human can-cers, can direct CBP to bind preerentially to NF-
κ
B andnot p53, thereby avoring prolieration and survival overp53-dependent apoptosis (Huang et al., 2007). There isalso crosstalk between p53 and the NF-
κ
B subunit p52.Under some conditions, p52 can be recruited directly top53 target promoters, leading to repression o
 p21
andactivation o proapoptotic
DR5
and
PUMA
(Schumm etal., 2006), thus tipping the balance toward apoptosis andaway rom cell cycle arrest. A number o additional p53-interacting proteins,including the p63 and p73 members o the p53 amily,can also modulate promoter choice by p53, even thoughthe exact underlying mechanisms remain to be eluci-dated (Laptenko and Prives, 2006).In their new work, Das et al. (2007) report that the zincnger protein Hz, encoded by a gene previously shown tobe a p53 target (Sugimoto et al., 2006), directly interactswith the p53 DBD, inducing preerential expression o p53target genes that block the cell cycle. Thus, Hz avors thetransactivation o
 p21
and
14-3-3
σ
genes while simultane-ously attenuating transcription o proapoptotic genes suchas
Bax
,
Perp
,
Puma and Noxa
(Das et al., 2007). The
Mdm2
 
Figur 1. Diffrtial Rgulatio of p53Targt G
In response to mild reparable damage, the tu-mor suppressor protein p53 is believed to trig-ger transient cell cycle arrest allowing sucienttime or repair o the damage and re-entry into anormal cell cycle. In contrast, severe, extendedor irreparable DNA damage will oten lead toapoptosis. These dierent ates are largely or-chestrated through the dierential activation odistinct subsets o p53 target genes. The bottompart o the gure lists previously known p53-in-teracting proteins and covalent p53 modica-tions reported to modulate the choice betweendierent subsets o target genes. The upperpart o the gure depicts the new ndings byDas et al. (2007) and Tanaka et al. (2007). Spe-cically, binding o the Hz zinc nger protein top53 avors its association with the promoters ogrowth-inhibitory genes, and disavors its asso-ciation with apoptotic genes. In contrast, CASassociates with p53 on the chromatin o promot-ers o several proapoptotic genes. This relievesthe inhibitory H3K27 methylation (K27meth)within the transcribed region o those genes,augments their transcription, and acilitatesapoptosis.
 
Cell
130
, August 24, 2007 ©2007 Elsevier Inc.
599
gene, which belongs to neither group and encodes a reg-ulator o p53, is not aected either way. Following short-term etoposide treatment to induce mild DNA damage,Hz-bound p53 engages proarrest but not proapoptotictargets. However, in similarly treated Hz-decient cellsp53 is detected primarily on proapoptotic targets. Remark-ably, ater prolonged etoposide treatment, which infictsextensive DNA damage, Hz undergoes proteasomal deg-radation. The resulting reduction in Hz levels now enablesactivation o proapoptotic genes, providing an appealingexplanation or the observation that extended damage trig-gers a switch rom a growth inhibitory transcriptional pro-gram to a proapoptotic one (Figure 1). As anticipated romits remarkable ability to instruct p53 to distinguish betweenthe two classes o target genes, Hz has a proound impacton cell ate decisions downstream o p53 activation: in itsabsence, even a mild genotoxic insult is sucient to trig-ger apoptosis. It will be o particular interest to nd outto whether alterations in Hz expression or activity areinvolved in human tumors, particularly those that retain awild-type
 p53
gene.
Regulation o p53 by Covalent Modifcations
Covalent modications o p53 may also change targetgene preerences, possibly by imposing conormationalchanges in p53 that encourage selective recognitiono dierent p53REs. It has been suggested that p53mutants that are able to activate only a subset o targetsmay be “locked” into a particular conormation that onlyrecognizes particular types o promoters. Wild-type p53,however, is conceivably fexible enough to go betweendierent conormations, thereby allowing diverse pro-moter recognition (Kim and Deppert, 2003). The list oreported post-translational modications on p53 is longand continuously growing, and includes phosphoryla-tion o multiple serine (Ser) and threonine (Thr) residues,acetylation, mono- and polyubiquitylation, sumoylation,neddylation and more.Much recent attention has ocused on p53 phos-phorylation on Ser46, which specically avors trans-activation o proapoptotic genes (Shmueli and Oren,2007). Indeed, mutation o Ser46 to Ala reduces the abil-ity o p53 to transactivate proapoptotic genes such as
 p53AIP1
,
Noxa
,
Dr5
,
Pidd
,
Perp and PUMA
and to triggerapoptosis, but not cell cycle arrest, in transected cellsas well as cells derived rom Ala46 knock-in mice (Fenget al., 2006; Oda et al., 2000). Interestingly, a naturallyoccurring p53-46F mutant mimics Ser46 phosphoryla-tion and specically induces p53 proapoptotic targetgenes, including
Noxa
,
 p53AIP1
and
 p53RFP
(Nakamuraet al., 2006), in keeping with the notion that phosphoryla-tion o Ser46 is key to p53 cell ate choice.Ser46 is the target o several kinases, including HIPK2,DYRK2, protein kinase C
δ
and p38 (Shmueli and Oren,2007). These kinases preerentially phosphorylate Ser46in response to extensive DNA damage, thereby contrib-uting to the increased likelihood o cell death under suchconditions. Although sharing a common target on p53,the mechanisms that direct the individual kinases to p53upon severe genotoxic damage vary greatly. For instance,whereas such damage drives DYRK2 rom the cytoplasminto the nucleus, granting it access to its p53 substrate,HIPK2 benets rom a more intricate process, wherein itslevels are increased owing to its release rom Mdm2-medi-ated proteasomal degradation (Shmueli and Oren, 2007).How is target gene choice dictated by phosphorylationo Ser46 or o other residues lying outside the p53 DBD?One possibility is that such modications change the over-all conormation o p53, thereby also aecting the DBD. Alternatively, by modulating coactivator binding, they mayindirectly aect chromatin states in the vicinity o p53REs,avoring the activation o particular genes over others. Acetylation also plays a role in dictating the targetpreerences o p53. Lysine 120 (K120) o p53 is some-times mutated in human cancers. Remarkably, tumor-derived K120R mutations abrogate p53-mediated apop-tosis, but not cell cycle arrest. In response to severeDNA damage, K120 is acetylated by the MYST amily oacetyl transerases, MOF and TIP60 (Sykes et al., 2006;Tang et al., 2006). This acetylated orm accumulatespreerentially on proapoptotic promoters, such as
Bax
 and
PUMA
, and presumably serves to recruit other p53coactors necessary to override the transcriptional bar-riers in proapoptotic genes.Recently, it has been reported that Lysine 320 (K320)o p53 is also important or the lie-death decision. Com-petition between acytelation and ubiquitylation at thissite directs cell ate toward apoptosis or growth arrest,respectively (Le Cam et al., 2006). Although ubiquity-lation is oten used to mark proteins or proteasomaldegradation, modication o K320 by the E3 ubiquitinligase E4F1, which promotes K48-type ubiquitylation onchromatin-bound p53, competes with PCAF-mediatedacetylation and thereby causes activation o proarrestgenes such as
 p21
and
cyclin G1
(Figure 1).Competition between acetylation and ubiquitylation alsooccurs on numerous additional lysines, located within theC-terminal part o p53. Depending on the extent o ubiqui-tylation, ubiquitylation may either promote p53 degrada-tion or export into the cytoplasm, in both cases reducingthe amount o nuclear p53 available or DNA binding. Con-versely, acetylation on these lysines can stabilize p53 andaugment its interaction with DNA within the nucleus. Atrst approximation, acetylation will thus benet selectivelythose target genes whose activation requires higher levelso p53. The dynamic nature o p53 acetylation, involving amultitude o histone acetyltranserases (HATs) and histonedeactylases (HDACs), endows it with enhanced potential tomodulate p53 target gene choice.
Manipulation o Chromatin by p53
Binding o p53 to promoter regions presumably recruitsactors that act locally on chromatin to “open” the geneor transcription. Thus, the p300/CBP HATs have beenimplicated as physiological regulators o p53-mediatedtranscription. In addition to targeting chromatin compo-

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