the tp53 gene , which encodes p53 , is one of the most frequently mutated genes in human cancers . the p53 protein has broad range of biological functions , including regulation of the cell cycle , apoptosis , senescence , dna metabolism , angiogenesis , cellular differentiation , and the immune response . numerous publications have reported various functions of p53 including transcriptional , posttranscriptional , and posttranslational roles . in this paper , we will focus on issues concerning p53 and application of p53-based cancer therapies . as reviewed by vousden and prives , numerous studies have shown p53 to be a transcription factor that targets many genes and micrornas in response to cellar stress . the key role of p53 as a tumor suppressor is to block cell cycle progression and/or to induce apoptosis , in response to cellular stresses such as dna damage . impaired p53 activity promotes the accumulation of dna damage in cells , which leads to a cancer phenotype . as a transcription factor , p53 forms a diverse and complex gene regulatory network . there has been extensive investigation to clarify the target sequences that p53 recognizes , the p53 response element ( re ) , as recently reviewed by riley et al . p53 has a very wide range of biological activities , so this review will focus on the role of p53 as a tumor suppressor and its implications for cancer therapy . more than 26,000 somatic mutation data of p53 appear in the international agency for research on cancer ( iarc ) tp53 database version r14 ( http://www-p53.iarc.fr/ ) . the frequency of tp53 mutation varies from ~10% ( hematopoietic malignancies ) to 5070% ( ovarian , colorectal , and head and neck malignancies ) . germline mutation of tp53 causes li - fraumeni syndrome , which is a familial cancer syndrome including breast cancer , soft tissue sarcoma , and various other types of cancer . most tp53 mutations in human cancers result in mutations within the dna - binding domain , thus preventing p53 from transcribing its target genes . however , mutant p53 has not only led to a loss of normal function of the wild - type protein but also led to new abilities to promote cancer . the first report of this gain of function by mutant p53 was the observation that transfection of mutant p53 into p53-null cells enhances tumor formation in mice . when p53 responds to dna damage , it elicits either cell cycle arrest or apoptosis . it was shown in 1991 that induction of wild - type p53 can induce apoptosis in leukemia cells . mice that have a specific p53 mutant lack the ability to induce cell cycle arrest , but retain the ability to induce apoptosis , allowing them to efficiently suppress oncogene - induced tumors , thus suggesting that the proapoptotic function of p53 may play a more important role in its antitumor effects than in its induction of cell cycle arrest . numerous reports have described the mechanism by which p53 induces apoptosis . as p53 functions mainly as a transcription factor , it is important to explore the genes regulated by p53 that contribute to the regulation of apoptosis . early studies showed that wild - type p53 can bind the bax gene promoter region and regulate bax gene transcription [ 12 , 13 ] . bax is a member of the bcl-2 family , which forms heterodimers with bcl-2 , inhibiting its activity . the bcl-2 protein family plays an important role in apoptosis and cancer [ 15 , 16 ] . for example , bcl-2 controls the release of cytochrome c from the mitochondria , which activates the apoptotic pathway by activating caspase 9 . several human cancers , including colon and stomach cancer , have altered expression of bcl-2 [ 1719 ] . however , the importance of the expression level of bcl-2 on the prognosis of cancer patients is still being investigated . the contribution of bax expression to the prognosis of cancer patients and the response to therapy is also unclear . in breast cancer , a study showed that a low level of expression of bax is associated with a poor prognosis , whereas other reports have shown no correlation between the bax expression level and prognosis . cd95 ( also called fas and apo-1 ) is a  death receptor  indicating its major role in apoptosis . the first report of cd95 showed that an anti - cd95 antibody reduced the growth of human b - cell xenograft tumors . since then , numerous reports have been published about the cd95-induced signaling pathway in apoptosis . cytotoxic agents , such as chemotherapeutic drugs , can induce apoptosis in drug - sensitive cells . several reports have indicated the cd95 pathway to play an important role in apoptosis induced by cytotoxic agents , and that this system involves the activation of wild - type p53 [ 23 , 24 ] . several bh3-only proteins have been identified , and p53 acts as a transcription factor for puma [ 26 , 27 ] and noxa , which both belong to this class . puma may play a pivotal role in determining cell fate ( programmed cell death versus cell cycle arrest ) in response to p53 activation . a report about puma knockout mice   showed that knockout of puma recapitulates the apoptotic deficiency observed in p53 knockout mice . because evading apoptosis is one of the hallmarks of cancer , puma may also play an important role during carcinogenesis . recent reports [ 31 , 32 ] have shown , however , that in certain situations , apoptosis can promote carcinogenesis . puma - deficient hematopoietic stem cells are protected from gamma - irradiation - induced cell death , which reduces compensatory proliferation and replication . on the other hand , wild - type mice experience massive cell death when they received gamma irradiation , which subsequently led to repopulation of the region by stem / progenitor cells . these reports indicate that the homeostasis stem / progenitor structure of tissue may suppress tumor formation . this phenomenon will need to be confirmed , but should be kept in mind when treating patients with strategies such as chemotherapy and/or radiation . the p53 protein suppresses tumor formation not only by inducing apoptosis but also by causing cell cycle arrest . depending on the type of cellular stress , p53 can induce g1 arrest through activation of transcription of the cyclin - dependent kinase inhibitor p21 . however , transient cell cycle may not lead to tumor eradication , because a cell with oncogenic potential that can not be repaired may resume proliferation . therefore , the other mechanism , cellular senescence , may play an important role in p53-mediated tumor suppression . there are many reports regarding the correlation between tumor development , p53 , and senescence [ 35 , 36 ] . the inactivation of p53 , as is present in most human cancers , allows cells to evade cellar senescence , thus resulting in macrolevel tumor development . p53 also seems to prevent premalignant lesions from developing into malignant tumors by activating senescence programs . cellular senescence induced by p53 is important not only for cancer prevention but also for the anticancer effect induced by any wild - type p53 introduced in established tumors . xue et al . constructed a mouse model of liver cancer with conditionally regulated endogeneous p53 . interestingly , the primary response to p53 was not apoptosis , but the induction of a cellar senescence program . we have reviewed two important roles of p53 as a tumor suppressor . among the various functions of p53 , apoptosis and senescence however , precisely how p53 determines whether or not the activation of the senescence program or the apoptosis program occurs still remains to be elucidated . this question is especially important for the development of p53-based cancer therapy , including approaches in combination with conventional chemotherapy . indeed , it has been reported that some types of breast cancer are protected from cytotoxic chemotherapeutic agents by endogeneous p53 . therefore , multiple factors , such as the quality and quantity of cellular stress , the tissue type , and the cellar microenvironment , determine the fate of the cell . vousden and prives proposed a model wherein the decision between life and death can be determined by the extent of damage or the duration of stress .   in their model , a low level of stress which can be repaired elicits a dna repair / survival response , while a high level of stress that can not be repaired induces an apoptotic or senescence response . this dual nature of p53 , killer and protector , indicates the possibility that p53 may also act as tumor promoter . the antiapoptotic function of p53 may lead to the survival of damaged cells , which may increase the possibility for malignant transformation ( figure 1 ) . because most , if not all , human cancers harbor altered p53 , the concept of restoration of p53 for cancer therapy is very attractive . an animal model showed the reactivation of wild - type p53 to result in efficient tumor regression , including regression of lymphoma [ 40 , 41 ] and liver carcinoma . there is class of small molecules that reactivate the wild - type functions of mutant p53 . phikan083 is a carbazole derivative found from in silico screening of the crystal structure of p53 . by binding mutated p53 , phikan083 raises the melting temperature of mutated p53 , which results in the reactivation of its function . prima-1 is another small molecule identified by cell - based screening which restored sequence - specific dna binding and the active conformation of p53 . cp-31398 is also a small molecule that can restore the protein folding of mutated p53 to a more natural conformation that permits a wild - type function . targeting mdm2 for p53 stabilization seems to be promising , so many reports on targeting mdm2 or the mdm2-p53 have been published . for example , the nutlins are cis - imidazoline compounds that act as antagonists of the mdm2-p53 interaction . analysis of the crystal structure showed that nutlin binds in the pocket of mdm2 to prevent the p53-mdm2 interaction . nutlin can activate the p53 pathway , thereby inducing cancer cells and xenograft tumors in mice to undergo cell cycle arrest , apoptosis , and growth inhibition . apoptosis and cell cycle arrest were observed in xenograft tumors which resulted in tumor regression .   however , mdm2 inhibition and p53 activation in normal tissue may be harmful . moreover , p53 triggered fatal pathologies that included the ablation of classically radiosensitive tissues . tenovin acts as an inhibitor of the protein - deacetylating activities of sirt1 and sirt2 . the intraperitoneal administration of tenovin-6 has been demonstrated to induce a regression of xenograft tumors in a mouse mode . issaeva et al . screened a chemical library and found the small molecule rita ( reactivation of p53 and induction of tumor cell apoptosis ) , which binds to p53 and inhibits the p53-mdm2 interaction both in vitro and in vivo . they also found that the p53 released from mdm2 by rita promotes p21 and hnrnp k ( a p53 cofactor ) , thus implying that p21 plays a major role in regulating the cancer cell fate after p53 reactivation   ( figure 2 ) . the small molecule pifithrin - alpha can block p53-dependent transcriptional activity and protect mice from the lethal side effects associated with anticancer treatment . if we can avoid dose - limiting genotoxic stress to normal cells during chemotherapy or radiotherapy for cancer , it will thus allow a higher dose to be used for patients who are not sufficiently responsive to conventional chemotherapy . the first p53-based gene therapy was reported in 1996 . a retroviral vector containing the wild - type p53 gene under the control of an actin promoter was injected directly into tumors of nonsmall cell lung cancer patients . after development of a replication - defective recombinant p53 virus ( ad5cmv - p53 ) , many clinical trials have been performed , including one in esophageal cancer patients . a few trials reached phase iii , but final approval from the fda tumor - associated antigen - specific cytotoxic t lymphocyte can mediate immune response of host against cancer in vivo . p53 protein , especially targeting missense mutation of p53 , can be candidate of tumor antigen . some cancer patients have antibodies against p53 , the frequency and clinical significance are still under debate . reported clinical trials of a p53-specific synthetic long peptide ( p53-slp ) vaccine for metastatic colorectal cancer patients . toxicity was tolerable , and p53-specific immune response was detected in 9 of 10 patients . p53-specific t - cell reactivity persisted more than 6 month in 6 of 9 patients . although the trial was phase i / ii , the clinical benefit may be hard to obtain because most patients had t - helper cells that lacked key cytokines . preclinical phase i/ ii trial of ingn-225 ( introgen ) , a p53-modified adenovirus - induced dendritic cell vaccine for small cell lung cancer ( sclc ) patients , has been reported . ingn-225 was well tolerated and induced p53-specific immune response in 18/43 ( 41.8% ) patients and sensitized sclc to subsequent chemotherapy . in this paper , we focused on the functions of p53 and clinical applications targeting p53 for cancer therapy . however , despite recent advances in the research on p53 's cytoplasmic function , it appears that various roles remain to be elucidated other than its function as a nuclear factor . p53 has been reported to induce apoptosis independent of its transcription of genes as early as 1994 . surprisingly , activated p53 can induce apoptosis in the cytoplasm by a bax - dependent mechanism . the next generation of p53-based cancer therapeutic approaches should therefore be developed to take advantage of this cytosolic function . this may be safer than regulating the transcription modulation of wild - type p53 , which can induce both prosurvival and proapoptotic effects in tumor cells , as discussed above . recent reports have showed that p53 regulates the process of self - renewal of neural stem cells   and hematopoietic stem cells . the cancer stem model insists that tumors are maintained by a small population of cancer stem cells that can divide both symmetrically and asymmetrically . mammary stem cells with the targeted mutation of p53 have been reported to show the same properties as cancer stem cells . the reactivation of p53 restored the asymmetric cell division of cancer stem cells and induced tumor growth inhibition . as a result , further investigation of the link between the p53 function and cancer stem cells may therefore be one of the most important research fields for uncovering new paradigms in cancer therapy .
tp53 , encoding p53 , is one of the most famous tumor suppressor genes . 
 the majority of human cancers demonstrate the inactivation of the p53 pathway . 
 mutant p53 not only , no longer , functions as a tumor suppressor but can also exert tumor - promoting effects . 
 the basic function of p53 is to respond to cellular stress . 
 we herein review the recent advances in p53 research and focus on apoptosis , cell cycle arrest , and senescence in response to stress . 
 we also review the clinical applications of p53-based therapy for human cancer .