The cancer and its relationship to genes stand as one of the major area of study through which we can unlock the mysteries of cancer. There are several aspects of cancer and its biomedical studies are underway and have provided enormous knowledge. There are several notable similarities between infectious diseases and cancers, both were common and fearsome ailments, was shrouded in mystery and superstition. The revolutionary research in infectious disease foreshadowed a similar breakthrough in cancer research. James Watson, Francis Crick and their collaborators and the subsequent cracking of the genetic code opened the door to the explosion in molecular biological research. A cancer gene can be defined as a variant of a gene that increases cancer risk, or promotes the development of cancer. The discovery of oncogenes, together with improvements in cytogenetics, resulted in an amalgamation of these two fields of research and led to the dawning of an understanding of how cancers might result from the breakdown of normal cellular homeostatic mechanisms.
Cells also contain special genes called proto-oncogenes. These proto-oncogenes are responsible for programmed growth in development or repair. They play a major role in co-ordinating our growth from a single fertilized egg cell into an adult with 10 13 cells. When development or tissue repair is complete, the cell growth is switched off. Cancer-causing agents or spontaneous genetic mutation change the proto-oncogenes into potentially cancer-causing oncogenes, as they promote growth where and when they should not. Spontaneous genetic mutation increases as we get older as our DNA repair processes become less efficient. When an oncogene is active in a cell, the cell doesn't require growth signals to grow so that the "switched-on" mechanism of growth and repair continues instead of being "switched off " as it should be, and the cells that are produced do not later undergo apoptosis (self destruction) when they are not wanted
The p53 gene is the gene is associated with large number cancers. P53 gene was first identified in 1979 by major effort of Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old [2] , [3] . The human TP53 gene was cloned in 1984 [4] and further investigation revealed the full length clone in 1985. [5] It was shown at that time that this new found gene was responsible for many cellular responses to DNA damage, it varies from a transient growth arrest to allow the cell to repair the DNA damage, or it can be an instruction to the cell to undergo apoptosis if the damage was too great. p53 protein is a transcription factor that switches on expression of genes that regulate the cell cycle and cause growth arrest and apoptosis [6]
Prevalence of p53 Alterations in Human Cancers
p53 is an important tumour suppressor and have biological properties which affect the cell proliferation. p53 is a nuclear phosphoprotein which is a produced by TP53 gene. The p53 tumor-suppressor gene is the most striking example because it is mutated in about half of almost all types of cancer arising from a wide spectrum of tissues [7] . It is a type of cancer gene that is created by loss-of function mutations in a cell. The p53 protein functions are an integral part of cellular signals and then acts as a central link in a signal transduction network that responds to minimal mutations and other errors that can lead to cancers or other pathologies [8] . The activating mutations in oncogenes that generate oncogenic alleles from proto-oncogene precursors can also activate tumor suppressor genes, and the proteins they encode, are functionally inactivated by mutations which can lead to proliferation abnormalities. Among the genes that can be induced by p53 are the Cdk inhibitor p21Cip1, many other genes encoding proapoptotic proteins, and the p53 negative regulator Mdm2 (Hdm2 in humans) that plays a role in terminating the p53 response. Mdm2 binds directly to p53 to inhibit transcription, and it catalyzes p53 ubiquitination, targeting p53 for degradation. [9] It also been shown that p19Arf binds directly to Mdm2 to antagonize these functions [10] . Mutations in other genes that affect p53 includes are mutations affecting Hdm2, ARF, and a series of transcription factors that control ARF and p53 gene expression [11]
Activators of p53 and the subsequent pathways
Biological Properties of p53
The Biological properties of p53 gene and protein statuses both play a key role in the regulation of the cell cycle, cell cycle arrest, and apoptotic response [12] , [13] , [14] . p53 can be activated by various factors include lack of substrate like nucleotide. Ultra violet radiation, ionizing radiation, oncogenic signalling, hypoxia and blockage of transcription factors all can affect the p53. In initial response to cellular changes the half-life of the p53 protein which leads to accumulation of p53 in stressed cells. Then there takes place and conformational change, forces p53 to be activated as a transcription regulator in these cells. Abrogation of p53 function is sufficient to extend the replicative lifespan of human primary cells. It acts on cell cycle and proliferation by various pathways few of them are described below
Cell cycle inhibitors
P53 central role in the induction of apoptosis and cell-cycle arrest, p53 is one of the most important checkpoint proteins of cell survival and genomic integrity induced by a variety of different damage stimuli like DNA damage, oncogenic or hypoxic stress. [15] Once the p53 is activated it binds to DNA and activates expression of several genes which encodes for p21. One of these genes include WAF1/CIP1 which binds to the G1-S/CDK (CDK2) and S/CDK complexes inhibiting their activity. These molecules are important for the G1/S transition in the cell cycle. When p21(WAF1) is complexed with CDK2 the cell cannot continue to complete cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will loose its inhibitory property for cell division. This will allow cells to divide uncontrollably and will cause neoplasia. [16] Another pathway is p53 dependent suppression of EZH2 expression, which is a novel pathway that contributes to p53-mediated G2/M arrest [17] . There are other links which can influence the cell proliferation is via interlink with Retinoblastoma gene pathway. The ability of deregulated E2F to induce ARF transcription provides one connection between the RB pathway and p53 [18] , [19] and may help to explain why most tumours have defects in the p53 pathway. Overexpression of E2F in established cell lines lacking ARF or p53 can enforce S phase entry even in the absence of mitogenic stimulation [20] , [21] , [22] but nonimmortal human diploid fibroblasts instead undergo an ARF-dependent p53 response leading to G1 phase arrest and, later, to apoptosis [23]
P53 & DNA repair
p53 levels are kept low through a continuous degradation of p53 in an unstressed cell. Mdm2 , which is itself a product of p53, binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. This is one means by which p53 is stabilized in response to oncogenic insults. Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of trancriptional coactivators, like p300 or PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis. [24] Some oncogenes can also stimulate the transcription of proteins which bind to MDM2 and inhibit its activity.Similarly, Jade1 has been found to stabilize pVHL, the product of the von Hippel-Lindau tumor suppressor gene, which in turn can stabilize and activate p53 [25]
P53 & transcription factors
p53 can induce apoptosis via transcription-dependent and transcription-independent functions [26] .p53 is its ability to activate transcription from promoters containing p53 response elements. [27] , [28] There are a number of likely p53 target genes that have been identified, including GADD45, mdm2 , p21/WAF1 , cyclin G , bax and IGFBP3 [29] , [30] , [31] , [32] , [33] , [34] . p53 mediates its pro-apoptotic response via transcriptional activation of pro-apoptotic target genes, such as BAX and PUMA, and trans-repression of pro-survival proteins. The p53 tumour suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumours overproduce MDM2 to impair p53 function. p53 is activated upon cellular stress such as DNA damage and the presence of oncogenes. SMAD family that are activated by TGF-β, leading to inhibition of cell proliferation. SMAD family can activates p21 & p27 which in turn can affect the functions of CDK2 and cyclin E which can alter cell proliferation. The p53 that produces P21 that has the same action as P16 in inhibiting the action of cdk4/cyclin D
P53 & angiogenesis
Tumourogenesis is associated with angiogenesis; mutations in TP53 are associated with an increase in tumor angiogenesis [35] . It has been shown that hypoxia can alter the expression of miRNA and that miRNA can alter HIF-1α expression in vitro [36] ,. Recent evidence suggests that antiangiogenic therapy is sensitive to p53 status in tumors, implicating a role for p53 in the regulation of angiogenesis. Here we show that p53 transcriptionally activates the α(II) collagen prolyl-4-hydroxylase [α(II)PH] gene, resulting in the extracellular release of antiangiogenic fragments of collagen type 4 and 18. Conditioned media from cells ectopically expressing either p53 or α(II)PH selectively inhibited growth of primary human endothelial cells. When expressed intracellularly or exogenously delivered, α(II)PH significantly inhibited tumor growth in mice. This reveal a genetic and biochemical linkage between the p53 tumor suppressor pathway and the synthesis of antiangiogenic collagen fragments. [37] , [38]
p53 targeted Therapies
Defects in apoptosis and cell cycle checkpoint control not only affect tumour development, but also contribute to multidrug resistance. Restoration of p53 function in p53 null tumors, which can potentially be achieved through genetic or pharmacologic methods, can directly induce apoptosis and re-establish responses to cytotoxic drugs , Pharmacological development of selective inhibitors of these pathways has long been underway, and many are already in clinical trials for cancer treatment. Cdk inhibitors , , might also prove useful in treating tumours that overexpress cyclin D1-Cdk4 or that have lost INK4a function. Similarly in p53 and angiogenesis cancers with mutations inTP53 and increased hypoxia
signaling may be more susceptible to antiangiogenic therapy than tumors with an intact p53 pathway. , There are various achievements, which have shown promising results in targeting the p53 genes including vaccines. [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48]
As the advancement in the field we hope that by the use of these specific inhibitors we can make our way forward in reducing the side effects and enhance the efficacy of treatment.
