Abstract
p53 as a tumor suppressor, assumes a crucial part in tumor suppression. The most generally mutated gene in cancer is TP53. As a transcription factor, p53 for the most part applies its part in tumor suppression through transcriptional control of its downstream target genes. Therefore, p53 and its objective genes structure a complex p53 signaling pathway to control a wide assortment of biological procedures to counteract tumorigenesis. Late studies have uncovered that addetively to apoptosis, cell cycle arrest and senescence, p53’s abilities in the regulation of energy metabolism and anti-oxidant defense contribute altogether to its part in tumor suppression. Concentrates further demonstrate that numerous tumor-related mutant p53 proteins not just lose tumor suppressive activities of wild-type p53, additionally acquire new oncogenic functions that are autonomous of wild-type p53, involving advancing tumor cell proliferation, survival, metabolic alterations, angiogenesis, and metastasis, which are characterized as mutant p53 gain of function. The continuous loss of wild-type p53 activities and the gain of function of mutant p53 in human cancer cells make p53 a to a great degree appealing focus for cancer treatment. Diverse techniques and some small molecule medications are being produced for the p53-based tumor treatment. Here, I review the mechanisms of p53 in tumor suppression and gain of function mutant p53 in tumor advancement, and also the late advances in the improvement of the p53-based tumor treatment.
Introduction
One of the most well known tumor suppressor p53, which is encoded by the TP53 gene, is found in an inactivated state in approximately half of all cancers. As it is reported, the TP53 gene, is one of the most frequently mutated genes in human cancers [1,2]. p53 mutations happen in each sort of tumor and in more than half of all tumors. Nearly 30%-50% of p53 mutations present in lung, esophageal, colorectal, head and neck, and ovarian cancers, an in nearly 5% of p53 mutations are found in leukemia, sarcoma, melanoma, testicular cancer and cervical cancer [3]. Mutant p53 cannot function as a tumor suppressor anymore and in addition to this, it can be function as a oncogene when it is started to overexpressed and has a tumor-promoting effect. As a transcription factor, a wild type p53 pathway affects a great variety of biological processes such as cell cycle arrest, DNA repairing mechanism, apoptosis, senesence, angiogenesis, immune response, energy metabolism and anti-oxidant defense to aver tumorigenesis [1,3,4].
In the malignancies refered at above with low p53 mutation rates, oftenly, p53 becomes inactivated by some difference mechanisms. Case in point, p53 is regularly inactivated and debased by human papillomavirus E6 protein (HPV-E6) in cervical cancer [3]. MDM2 (mouse double minute 2 homolog) which is the most crucial negative controller of p53, is often enhanced and also, overexpressed in sarcoma, causing the degradation of p53 protein [5]. It was evaluated that around 80% of human tumors have non-functional p53. In addition, the reason for Li-Fraumeni disorder, which is a hereditary predisposition syndrome, is the germline mutations of p53 [3]. Moreover, p53 knock out mice prompts the advancement of tumors, involving lymphomas and sarcomas, at younger ages. Generally the human tumors involving p53 mutations are missense mutations which has a result of full-length mutant p53 proteins [2]. Late studies have exhibit that numerous tumor-related mutant p53 proteins not just lose p53 wild-type tumor suppressive functions, additionally increase new oncogenic funsctions which are autonomous of wild-type p53, covering stimulation of tumor cell proliferation, against apoptosis, angiogenesis, metastasis, and metabolic changes which are characterized as mutant p53 addition of-capacity.
Fundamentally, p53 tumor suppressor plays a role in combining multiple signals of stress into a sequence of different antiproliferative responses [6]. As mentioned earlier, because of p53’s pivotal function in tumor suppression, it is very important to understand its mechanism to find new ways to treat cancer via revitalizing the inactive p53-dependent apoptotic pathway. In this paper, I will focus on the mechanism of p53 signaling pathway in tumor suppression, its gain of function mutations in cancer and the cancer threapy approaches based on p53 pathway. References related on this subject are showed in the convenient parts of this paper.
The Signaling Pathway of p53
p53 as a transcription factor, usually functions through transcriptional regulation of its target genes. In the condition without any stress, the p53 protein is kept up at a low level in cells by the pathway involving MDM2, which is an E3 ubiquitin ligase that controls p53 degradation [1,3]. Under the stressed conditions involving DNA damage, ribonucleotide consumption, starvation, hypoxia and oncogene initation, p53 is balanced out through post-translational changes by a broad range of enzymes such as kinases, phosphatates, acetyltransferases, deacetylases, ubiquitin ligases, deubiquitinases, methylases and sumoylases. Once enacted, p53 binds to a particular DNA sequence which is termed as the p53-responsive component, in its target genes to manage their expression [2]. The p53-responsive component consists of RRRCWWGYYY (spacer of 0-21 nucleotides) RRRCWWGYYY, where R is a purine, W is A or T, and Y is a pyrimidine. p53 controls an extensive variety of cell natural processes to keep up genomic integrity and counteract tumor formation, comprising cell cycle arrest, apoptosis, senesence, energy metabolism, anti-oxidant defese and autophagy and so on (Figure 1).
p53’s Tumor Suppressive Functions
Apoptosis, cell cycle arrest, and senesence have been generally acknowledged as the primary mechanisms for p53’s tumor suppressive function among other cellular proccesses that are controlled by p53. Moreover, p53’s most extremely contemplated function is apoptosis. It was initially reported in mouse thymocytes in beam of light. Thenceforth, the p53-dependant apoptosis has been accounted for in a broad range of cells because of various signals of different stresses. When the cell is actuated by these stress signals, p53 transcriptionally prompts a gathering of target genes which are included in apoptosis, comprising PUMA (p53 up-controlled modulator of apoptosis), Bax (BCL-2 related X protein), Noxa (PMAIP1), PIG3 (tumor protein p53 inducible protein 3), Killer/DR5 (tumor necrosis factor receptor superfamily, member 10b), Fas (Fas cell surface death receptor), Perp (p53 apoptosis effector related to PMP-22), and p53AIP1 (tumor protein p53 regulated apoptosis including protein 1), directing apoptosis [3]. Among these p53 targets included in apoptosis, the PUMA appears to assume a more pivotal part following just loss of PUMA shows comparable apoptotic alterations as loss of p53 in illuminated T-lymphocytes in mouse models. Later contemplates have demonstrated that p53 can likewise control apoptosis through a transcription-independent mechanism. In a stressed condition, certain amount of the p53 protein translocates to mitochondria, where p53 interacts with anti-apoptotic Bcl-xL and Bcl-2 to hinder their functions, ending with the arrival of cytochrome c from the mitochondria and hence, actuates apoptosis.
Prompting the cell cycle arrest is another widely studied function of p53. Because of different stress signals, p53 transactivates some particular target genes,ending in cellular growth arrest at distinctive cell cycle checkpoints to avert the extension and gathering of DNA damage and mutations. p53 can stimulate G1 arrest through transcriptional inducement of p21, which is a cyclin-dependent kinase inhibitor depending on the type of cellular stress [1,3]. This mechanism is well known and has been comprehensively studied. In addition to this, it is reported that, p53 controls the G2/M transition by transcriptionally activating GADD45 (growth arrest and DNA-Damage-inducible 45) and 14-3-3s (thyrosine 3-monooxygenase/trytophan 5-monooxygenase activation protein, sigma polypeptide) and, thereby blocking cell entry into mitosis by hindrance of Cdc2. Cdc2 necessities to bind to cyclin B1 in order to function [1]. Restraint of cyclin B1 by p53 additionally arrests of cells in G2. The transitory G1 or G2 arrest actuated by signals of stresss, permits cells to survive until harm has been repaired or stress signals have been removed.
Another crucial function of p53 is promting senescence. Numerous DNA-damaging agents that are utilized as a part of chemotherapy can enact p53 and promp senescence. Furthormore, lately it was reported that reactivation of p53 in p53-insufficient tumors totally quells tumor development through senescence in a mouse live tumor model [3]. Nevertheless, the mechanism by which p53 affects senescence is not as clear as the systems for apoptosis and cell cycle arrest. Numerous senescence signals initiate p53, which thusly, transactivates p21 and instigates p53-dependent senescence. As of late, PAI-1 (plasminogen activator inhibitor-1) was accounted for to be another target gene included in the p53-dependent senescence [3].
Additevely to apoptosis, cell cycle arrest, and senescence, late studies have uncovered some extra systems for p53 in tumor suppression, involving regulation of cellular metabolism, anti-oxidant defense, autophagy, and microRNAs (miRNAs) [3]. As of late, metabolic alterations have been respected as a characteristic feature of tumor cells, which could be a key participant to tumorigenesis. p53 have two types of ways to affect energy metbolism to maintain the homeostasis; one is the up-regulation of mitochondrial oxidative phosphorylation and, two is the down-regulation of glycolysis in cells. p53 transcriptionally actuates its target SCO2 (synthesis of cytochrome c oxidase 2), AIF (apoptosis-inducing factor), and p53R2 (ribonucleotide reductase M2 B) to keep up the mitochondrial unity and advance mitochondrial oxidative phosphorylation. p53 likewise prompts the expression of mitochondrial glutaminase GLS2 to advance oxidative phosphorylation. In the meantime, p53 lessens glucose uptake through curbing the expression of GLUT1, 3, and 4 (glucose transporter 1, 3, and 4). Besides, p53 transcriptionally incites TIGAR (TP53 inducible glycolysis and apoptosis regulator) and Parkin (Parkin RBR E3 ubiquitin protein ligase) to restrain glycolysis. In addition to these, p53 was also accounted to bind and decrease the action of glucose-phosphate dehydrogenase, which is a rate-constraining enzyme in the pentose phosphate pathway, to down-control glucose metabolism [3].
Late concentrates likewise demonstrated that p53 shields cells from oxidation by decrasing intracellular receptive oxygen species (ROS), a noteworthy reason for DNA damage and genetic instability that contributes enormously to p53’s part as a tumor suppressor. p53 insufficiency in cells and mouse tissues results in the rise of intracellular ROS levels, which thusly prompts the expanded DNA oxidation and mutation rates in cells. These impacts can be significantly turned around by ectopic expression of Sestrins, which are p53 targets included in cancer prevention agent barrier, in p53 inadequacy cells. Moreover, the p53 knockout mice’s early onset tumors were prevented by dietary supplementation with anti-oxidant N-acetylcysteine [3]. p53 transcriptionally incites a gathering of anti-oxidant genes, involving sestrins 1/2, TIGAR, GPX1, ALDH4, GLS2, and Parkin, particularly under states of non-stress or low stress to decrease the intracellular levels of ROS and avert DNA damage promted by ROS to apply its anti-oxidant function.
Autophagy is a critical cellular catabolic procedure described by the arrangement of double-membrane autophagosomes around cytoplasmic segments focused for degradation such as old or damaged organelles. As of late, it has been proposed that autophagy might assume a dual part in tumorigenesis; autophagy assumes a critical role in keeping up genomic stability and tumor avoidance in normal cells and tissues, while autophagy can advance tumor cell survival and tumor progression in tumors. p53 has been accounted for to advance autophagy through distinctive mechanisms that might contribure to the role of p53 in tumor avoidance. p53 advances autophagy through restraint of the mTOR (mammalian focus of rapamycin) pathway,which is a basic negative controller of autophagy. p53 likewise impels the expression of a few genes, comprising DRAM (DNA-damage regulated autophagy modulator 1), PUMA, ISG20L1 (interferon-stimulated exonuclease gene 20 kDa-like 1), and Ei24 (etoposideinduced 2.4), to advance autophagy [3]. Also, p53 was reported to restrain autophagy in specific situations. For instance, cytoplasmic p53 hinders autophagy without enactment of p53 target genes in a few sorts of cells. Essentially, tumor-related mutant types of p53, particularly those situated in the cytoplasm, were additionally reported to repress autophagy (Figure 1).
Besides the transcriptional regulation of protein-coding genes, late studies have demonstrated that p53 can transcriptionally control the expression of miRNAs as another system for p53 to apply its tumor suppressive effects. miRNAs are a class of little (20-25 nucleotide) non-coding RNAs that assume a critical part in the post-transcriptional control of gene expression. The stimulation of the hindrance of translation and degradation of mRNAs are ensured by the miRNAs binding to 3’-UTRs. The miR-34 family members, which are miR-34a/b/c, were the first gathering of miRNAs that were distinguished as immediate p53 target genes [3]. The direct binding to the p53-responsive components of miR34-a/b/c’s promoters provides the control of their expression by p53. miR-34 family members suppress the expression of a few targets included in the regulation of cell cycle, cell proliferation and survival, involving cyclin E2, CDK4/6, and BCL2. Stimulation of p53-mediated apoptosis, cell cycle arrest, and senescence are provided by the ectopic expression of miR-34 family members. From that point forward, a gathering of miRNAs has been accounted for to be specifically prompted by p53, involving miR-145, miR-107, miR-192/194/215, miR-15a/16-1, miR-215, and let-7, to intercede the function of p53 in directing diverse biological processes, comprising cell cycle arrest, senescence, apoptosis, metabolism, mesenchymal-epithelial transition, and differentiation. Also, p53 advances the post-transcriptional maturation of particular miRNAs. Besides, p53 influences the miRNA target determination by controling RNA binding proteins such as RBM38 ( RNA-binding-motif protein 38), which rivals miRNAs for binding to 3’-UTRs of mRNAs of target genes [3].
With the recognizable proof of more elements of p53, a critical inquiry has been raised that which function is significant for p53’s part in tumor suppression. Numerous studies have been did to address this inquiry, and numerous fascinating perceptions have been made, but, there is no unmistakable response to this inquiry, and a few perceptions even give off an impression of being conflicting. For example while it is settled that p21 assumes a basic part in interceding p53’s part in inciting cell cycle arrest in a stressed condition, unlike p53-null mice, p21 null animals are not inclined to ahead of schedule onset tumorigenesis [3], recommending that the function of p53 in prompting cell cycle arrest does not contribute fundamentally to its part in tumor suppression. Interruption of apoptosis by Bcl-2 overexpression or loss of PUMA advanced Eµ-myc-actuated lymphomagenesis in mice. On the other hand, the Bcl-2 transgenic or PUMA knockout mice were not as tumorprone as p53 knockout mice, proposing that inciting apoptosis alone cannot intervene the tumor suppressive effect of p53 [3]. Mice expressing a mutant p53 (p53R172P) inadequate for p53-mediated apoptosis yet not cell cycle arrest and senescence were impervious to ahead of schedule onset tumorigenesis [3]. Mice expressing p53 (25, 26), a mutant p53 that covers two mutations at codons 25 and 26 and is inadeqaute for cell cycle arrest and apoptosis however not senescence, held the function to hinder KrasG12D-impelled lung carcinogenesis. In addition, p53 mutations in three acetylation locales (K117R+K161R+K162R) in mice weakened the p53-mediated apoptosis, cell cycle arrest, and senescence; notwithstanding, these mutations did not influence the activities of p53 to control energy metabolism and ROS production in mice. Conspicuously, the mice did not grow early onset lymphomas as p53 knockout mice, proposing that the control of energy metabolism and ROS prodcuction by p53 contributes fundamentally to the part of p53 in tumor suppression [3]. While it is still misty which function(s) of p53 is basic for p53 in tumor suppression, these discoveries recommended one plausibility that p53 may apply its role as tumor suppressor with unmistakable mechanisms in distinctive connections, involving diverse sorts of cells and tissues, distinctive hereditary background and microenvironment of cells, an in response to diverse sorts of stress signals. Despite everything it remains to a great extent vague how p53 specifically directs distinctive gatherings of target genes and starts diverse cell reactions to applt its tumor suppressive functtion ind distinctive sorts of cells and tissues because of distinctive stress signals. Moreover, late studies have reported that a gathering of proteins are included in adjustinf the determination of p53 target genes. As an example, hCAS/CSE1L (humal cellular apoptosis susceptibility protein) was accounted for to take up with the promoters of a subset of p53 target genes, for example, pro-apoptotic PIG3, however not p21 [3]. This impact is accomplished through the regulation of histone methylation and chromatin alteration of p53 target genes by hCAS/CSE1L [66]. ASSP1 and ASSP2 (apoptosis-stimulating of p53 proteins 1 and 2) tie to p53 protein and specifically empower the coupling of p53 to the promoters of p53 target genes included in apoptosis, for instance, PIG3 and Bax. This impact was definitely not declared for p53 target genes included in cell cycle arrest , for example, p21, despite the fact that the mechanism is indistinct. Hzf (hematopoietic zinc finger), which is a zinc-finger protein, straightforwardly interacted with the DNA-binding site of p53, and specially incites p53 target genes included in cell cycle arrest, for example, p21 and 14-3-3s [3]. Because of extensive signals of stress, Hzf is depraved by the proteasome debasement pathway, which thus prompts the transcriptional enactment of p53 targets included in apoptosis, for example, Bax, Noxa, and Perp. SLUG (snail family zinc finger 2) is prompted by p53 and alienates p53-mediated apoptosis activated by DNA damage. SLUG applies this defensive part by stifling p53 target PUMA. What’s more, lincRNA-p21, a vast intergenic non-coding RNA (lincRNA) was as of late reported to serve as a repressor in p53-dependent transcriptional reactions, which is intervened through the physical relationship with hnRNP-K [3]. This cooperation is required for appropriate genomic localization of hnRNP-K at curbed genes and control of p53-mediated apoptosis. Future studies will advance clarify the exact system by which p53 specifically directs distinctive cell reactions and facilitates these reactions in diverse settings to apply its part as a tumor suppressor.
Gain of Function of Mutant p53 in Cancers
p53’s function is significantly affected by the single amino acid changes in the p53 gene. In human tumors, missense mutations involve roughly 75% of all p53 changes [7]. This is incontrast to numerous other tumor suppressor genaes that experience erasure through the course of tumor initiation or development, for example PTEN, BRCA1, and Rb. Furthermore, five arginine residues in the p53 gene are examined as “mutational hotspots”; ending with mutant proteins that neglect to bind to sequence-specific DNA sites and in this way definetely modify the range of transcriptional activity [3,7]. At the point when wild-type and mutant p53 alleles present in a heterozygous condition in tumor cells, mutant p53 can obstruct the function of wild-type p53 through its dominant negative impact. On the other hand, p53 mutations are generally trailed by loss of heterozygosity in human malignancy, prompting the detection or mutation of the rest wild-type p53 allele. Throughout the time that the wild-type p53 protein is kept at a low level in cells by the proteasome debasement pathway under non-stressed situations, mutant p53 protein commonly accumulates to a high level in tumors and yet the essential mechanisms are not fully implied [3].
It has been all around recorded that numerous tumor-related mutant p53 proteins lose their tummor suppression effects, as well as build up new oncogenic activities, which is named as gain of function (GOF) of mutant p53 [3,8]. The main proof originated from the discoveries that transfection of mutant p53 in p53-null tumor cells enormously expanded the tumorigenicirt of those cells in nude mouse [3,7]. From that point forward, by ectopic expression of mutant p53 in p53-null tumor cells ar by knockdown of endogenous mutant p53 in tumor cells that have lost the wild-type p53 allele, and numerous studies have exhibited distinctive gain of function activities of mutant p53 contribute to malignant transformation by increasing cell proliferation, invasion, metastatic ability of cells, and chemoresistance [3,8]. As of late, the gain of function oncogenic exertions of mutant p53 were likewise obviously shown in two mutant p53 knock-in mice models. Mice expressing R172H or R270H mutp53 (proportionate to human R175H and R273H, individually) build up an adjusted range of tumors and more metastatic tumors contrasted and p53-/- mice [3].
Gain of Function of Mutant p53’s Mechanism
Latest studies have suggested the following certain mechanisms that contain acquisition of new oncogenic activities of mutant p53 (Figure 2).
Mutant p53 associates with p63 and p73
The first mechanism detected demonstrated that mutant p53 abolish the tumor suppressive activities of p63 and p73 which are the p53 family members [7]. The two structural and functional homologs of p53 are p63 and p73 [3]. p63 and p73 bind to and enact numerous target genes, and intervene cell cycle arrest, apoptosis, and senescence in reaction to stress. p63 and p73 were appeared to act as homotetramers and heterotetramers with one another, yet they do not appear as heterotetramers with wild-type p53. Moreover, certain types of mutant p53 were accounted for to interact with p63 and p73 through their DNA-binding domains to hinder the transcriptional functions of p63 and p73. The interplay between p63/p73 and mutant p53 are connected with numerous parts of the gain of function mutant p53, for instance, chemoresistance, invasion, migration and metastasis.
Mutant p53 binds to trancription factors to adjust their activities
It has been accounted for thath mutant p53 can interplay with other transcription factors and be enlisted to their binding sites to regulate the expression of their target genes [3]. For instance, mutant p53 has been appeared to interplay with trancription factor NF-Y, and up-direct the expression of NF-Y target genes. Mutant p53 was additionally addressed to bind to vitamin D receptor (VDR) and be enlisted to VDR-regulated genes to regulate their expression. Moreover, mutant p53 increases sp1 transcriptional function when it interplays with sp1 at the concord sp1 responsive components in the HIV-LTR [3]. Laltely, mutant p53 was accounted for cooperate with SREBP (sterol regulatory element-binding protein) group of transcription factors to direct the expression of genes in the mevalonate pathway to disturb tissue composition in breast cancer cells.
To change proteins functions mutant p53 interplays with them
Mutant p53 can appear as complex with some different proteins and influence their activities that advances to the gain of function of mutant p53 [3]. For instance, mutant p53 cooperates with MRE11, which is a DNA nuclease claimed for homologous recombination DNA repair. The interplay between MRE11 and mutant p53 advances genomic instability and tumor development. Also, mutant p53 interplays and colocalizes with PML (promyeloctic leukemia) protein, actuating mutant p53 transcription action in cells. In addition, mutanr p53 was addressed to interplay with topoisomerase 1, which keeps up DNA topology, ended with genomic instability and hyper-recombination. Prolyl isomerase Pin1, which controls conformational alterations of proteins to influence protein activity and stability, was accounted for to be an extra mutant p53-binding protein [3]. Pin1 collaborates with mutant p53 in Ras-dependent alteration. Pin1 advances the oncogenic function of mutant p53 to assist aggressiveness through mutant p53-dependent restraint of p63 and impelling of a mutant p53 trancriptional program, in breast cancer cells.
To change gene expression mutant p53 binds to DNA
Mutant p53 has been accounted for to up-control down-control various genes included in diverse parts of tumorigenesis, involving Myc, Fos, PCNA, IGF1R, EGR1, including NF-kB2, BCL-xL, IGF2, VEGFA, and so on. Through to transcriptional control of these genes, mutant p53 advances proliferation, anti-apoptosis, angiogenesis, and inflammation [3]. The capability of mutant p53 to bind specifically to DNA gives off an impression of being critical for mutant p53 in directing transcription of these genes, but no characterized mutant p53-responsive component has been outlined. In addition, it has been accounted for that mutant p53 binds directly to DNA in a DNA structure-particular mode. Case in point, mutant p53 has a high affection for nuclear matrix connection domains, which are very high AT-rich domains that intervene basic association of the chromatin and frequently adopt non-B DNA configurations. Moreover, mutant p53 was appeared to bind specifically and with high affection to non-B DNA.
Mutant p53 controls miRNAs
Late concentrates likewise showed that mutant p53 controls miRNAs, adding to its add of gain of function. Mutant p53 incites or stifles the expression of certain miRNAs to acquire new oncogenic functions. Case in point, mutant p53 specifically binds to the promoter of miR-130b and represses its transcription [3]. In endometrial cancer, as a negative controller of ZEB1, miR-130b advances epithelial–mesenchymal transition and invasion of cancer cell. In breast cancer, mutant p53 impels miR-155 to actuate invasion. MiR-155 quells the expression of zinc-finger transcriptional repressor ZNF652, which curbs the expression of proteins that advance invasion and metastasis, for example, TGFB1/2, EGFR, and SMAD2 [3,7]. Mutant p53 binds to the miR-27a promoter domain and stifles its expression. Since EGFR is an immediate focus of miR-27a, through quelling miR-27a, mutant p53 advances a supported EGF-actuated ERK1/2 initiation, along these lines advancing cell expansion and tumorigenesis. Besides, mutant p53 instigates miR-128-2, which targets E2F5, to improve chemoresistance in lung malignancy cells. Also, controlling the expression of miRNAs, mutant p53 likewise influences the actions of miRNAs. For instance, mutant p53 represses the actions of pri-miRNAs by Drosha, and in this manner declines the levels of certain developed miRNAs in cells, including miR-16-1, miR-143, and miR-145 [3]. These miRNAs have been appeared to adversely control cell cycle and cell expansion. Furthermore, mutant p53 was additionally addressed to stifle DICER1 expression through binding and inactivation of p63 (Figure 2).
Cancer Theraphy and p53
The p53 signaling pathway is assessed to be broken in approximately 80% of human tumors through alterations and different mechanisms thus, p53 is drastically focus for cancer treatment. Various studies have demonstrated that reactivation of p53 is disturbing for malignant cells. For example, re-expression of wild-type p53 in p-53 lacking tumor cells prompts apoptosis or senescence in cultured cells [3]. In mice models, re-presentation of wild-type p53 into p53-lacking tumors prompts tumor regression, while re-presentation of wild-type p53 into mutant p53-harboring tumors abolishes growth of tumor. Huge endeavors have been made to advance the p53-based cancer treatment amid the previous decade. Certain strategies have been created, involving ectopic expression of wild-type p53, activation of non-funtional wild-type p53, destabilization or inactivation of mutant p53, and reactivation of mutant p53 in cancer cells.
Gene therapy based on p53
The Adenovirus-mediated p53 gene transfer at gene theraphy based on p53 was initially reported in 1996 to treat non-small cell lung carcinoma [1,3]. Because of the thought of biosafety, the replication-impaired recombinant adenovirus expressing p53 (rAd-p53) was advanced later, which has a superior transduction efficiency and lower leveled harmfulness. In China, the rAd-p53, which has a brand name as gendicine, has been endorsed for clinical utilization for the head and neck cancer treatment.
Activation of wild-type p53 function by small molecules
As a key negative controller for p53, MDM2 is oftenly boosted and/or overexpressed in different tumors, which prompts the brokenness of p53 [3,9]. Through binding to the domain of MDM2 to obstruct the interplay between MDM2 and p53, Nutlin-3, which is a non-genotoxic small molecule, has been advanced, to hinder MDM2 and enact wild-type p53 in tumor cells. Nutlin-3 instigates p53-mediated cell cycle arrest, apoptosis, and other antitumor actions in different cultivated tumor cells and xenograft tumors in mouse in a wild-type p53-dependent way [3].Nutlin-3 is right now being tried in stage 1 clinical trail [10]. In addition to the small molecule Nutlin-3, another MDM2 inhibitor as a small molecule is MI-219. It can agitate p53-MDM2 binding, prompting the enacted p53 signaling and suppression of tumor development in animalistic models. Another small molecule RITA was accounted for to bind to p53, which disturbs the coupling of p53 with its negative controllers, ivolving MDM2 [1,3]. It has been demonstrated that RITA can actuate p53 signaling and suppress tumor development in vivo [3]. CP-31398 was accounted for to be another small molecule that balances out the wild-type p53 and advances its transcriptional actions in cells. Then again, a late study reported that CP-31398 causes harmfulness in liver and other tissues in animalistic models, proposing the need to adjust the structure of CP-31398 to decrease its toxicity.
Inactivation or destabilization of mutant p53 by small molecules
Mutant p53 is as often as possible gathered to abnormal levels in tumors and shows gain of function oncogenic actions. In this manner, inactivation or destabilization of mutant p53 is being advanced as a vital strategy for cancer treatment. Late studies demonstrated that HDAC6/Hsp90 signaling assumes an essential part in stabilizing mutant p53 in cancer cells. Restraint of HDAC6 or Hsp90 has been appeared to destabilize mutant p53 in tumor cells and decline tumorigenicity of cancer cells. Moreover, SAHA, which is a HDAC inhibitor, was appeared to destabilize mutant p53 in tumor cells [3]. To hinder the mutant p53-p73 coorperation, a small molecule RETRE has been accounted, and in this way discharges p73 and restores p73’s ability in transcriptional initiation. RETRA was appeared to transactivate p53 target genes in mutant p53-bearing tumors and avert the development of xenograft tumors in mice [3].
The reactivation of wild-type activity in mutant p53
Late studies have likewise prompted the recognizable proof of a class of small molecules that changes over mutant p53 proteins into structures that show wild-type p53 actions, along these lines permitting p53 to impel cell cycle arrest or apoptosis in cancer cells. PRIMA-1 is such a molecule, which can restore sequence specific DNA binding and change over mutant p53 configuration to wild-type, in this way prompting the transactivation of p53 target genes [3]. PRIMA-1 was accounted for to sensitize malignant cells to chemotherapy and hinder tumor development in vivo [3,9]. The analog of APR-246, the PRIMA-1, is being tried in stage I clinical trials in liver or prostate cancer patients [3,10]. Additevely to its ability yo stabilize and actuate wild-type p53, CP-31398 can likewise restore DNA-binding action and in this way the wild-type p53 ability to mutant p53 to restrain tumor cell development in culture and tumor development in animalistic models [3]. As of late, an allele-particular p53-reactivating compound NSC-319725 was distinguished, which can restore the wild-type structure and capacity to the R175H mutant p53. This compound affects broad apoptosis in R172H mutant p53 knock-in mice and hinders the development of xenograft tumors containing R175H mutant p53 in mice [3].
Conclusion
p53 has been a standout amongst the most widely considered proteins since its disclosure. In this review, I have concentrated on the activities of wild-type p53 and its gain of function mutants in cancer cells. In addition to the understood concepts of p53 in inciting cell cycle arrest, apoptosis, and senescence, later concentrates on have uncovered extra novel functions of p53 in tumor suppression, comprising the regulation of metabolism and anti-oxidant resistance. Despite everything it remains generally hazy how p53 specifically and/or coordinately controls these activities to apply its part in tumor avoidance and tumor treatment in diverse sorts of cells and tisssues. In spite of the fact that the theory of gain of function of mutant p53 has existed practically since the start of p53 exploration, just as of late, colossal endeavors have been made to exhibit that mutant p53 advances tumorigenesis through controling a wide range of parts of oncogenetic procedures. In any case, the basic systems for mutant p53 gain of function are not completely caught on. Besides, it is misty how diverse types of mutant p53 encounter upon tumorigenesis. Further understanding the mechanisms of p53 in tumor suppression and systems of gain of function of mutant p53 in tumor advancement will give novel targets and ways to deal with cancer treatment. As a conclusion, p53 keeps on developing and future studies on p53 will provide the advancement of cancer-particular p53-based therapy and new chemicals to fundamentally enhance cancer treatment.
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