There are two main ways by which p53 protein can act as tumor suppressor1 (Figure 1). The first way is to inhibit cell cycle progression, in which p53 plays a role of a transcription factor to regulate the expression of several gene products that involved in cell cycle.1 For example, p53 can turn on the transcription of p21 protein, which is a CDK inhibitor of the CDK2-cyclinE complex.2 This accumulation of p21 would greatly induce the G1 phase arrest.1 Also, p53 could impact cell ability to utilize dNTP during S phase of DNA replication. The inhibition of ribonucleotide reductase by p53 would lead to progress arrest due to the depletion of dNTP supply.1 Furthermore, p53 can cause G2 arrest by transcriptionally induce several other proteins such as CDK-cyclin inhibitors,2 such as 14-3-3?1 and GADD452 (growth arrest and DNA-damage inducible gene). Another way for p53 to suppress tumor is by regulating factors during cell apoptotic signaling.1 In the intrinsic apoptosis that mediated by mitochondria, the pro-apoptotic Bcl-2 family members (PUMA, NOXA, and bax) can be transcriptionally controlled by p53.1 It can also upregulate the extrinsic apoptotic signalling which associates with death receptor such as Fas.2 This increased expression of several death receptors along with the mitochondria pathway of apoptosis would eventually lead to the enhanced cell death of mutated cell.Besides these two main ways, p53 can also interfere with cell senescence and display the role of anti-oxidation agent.1 However, it has not been fully determined yet which mechanisms of p53 contribute the most to its tumor suppression function.B)Since p53 is a cell proliferation inhibitor gene, it has to be tightly regulated in normal cells. This regulation on p53 can be done by MDM2 protein. MDM2 is a p53-specific oncogenic E3 ubiquitin ligase, which can add molecules of ubiquitin onto p53 and lead to the facilitated degradation.3 Besides that, MDM2 can also bind to p53 at its transactivation domain to inhibit it directly.3 There are two scenarios for p53 to be regulated: monoubiquitination and polyubiquitination.4 When the activity of MDM2 is low in the nucleus, it would put only one ubiquitin onto the p53 and translocate it out of the nucleus into the cytoplasm and unable its ability to induce transcriptional activity.4 However, in the high level of MDM2 protein activity, the p53 would be polyubiquitinated and got degraded by proteasome completely.4 Moreover, MDM2 protein and p53 protein interact with each other in a negative feedback loop manner.3 As the MDM2 ubiquitinated p53, p53 itself would also increase the transcription of MDM2, which lead to MDM2 accumulation and inhibit p53 activity even more.3 However, when there is DNA damage or any oncogene signal present, the complex of MDM2 and p53 protein will then be modified or interfered.3 For instance, phosphorylation of the binding sites of proteins, phosphorylation on MDM2 so that it can’t ubiquitination, or binding of MDM2 inhibitor (Figure 2).Thus, for anti-cancer therapies or drugs, the inhibitory of MDM2 could be a very effective way to rapidly elevate p53 protein level in the cell, which would eventually lead to the cell cycle arrest and cell apoptosis, etc. In this way, the tumor cells might be controlled or even eliminated. C)Nutlin is a class of small-molecule antagonists of the p53-MDM2 binding complex.6 It was found that it can efficiently inhibit p53-MDM2 interaction by binding to MDM2 pocket that’s originally for p53 to bind6 (Figure 3). In this way, wild-type p53 protein induced pathway can be constantly activated and stabilized, eventually lead to cell cycle arrest and apoptosis.The crystallized structure of MDM2-p53 complex allows researchers to find a suitable antagonist compound.6 By screening different chemical compounds, researchers eventually discovered a class of cis-imidazoline compounds that could bind to MDM2 by acting as an analog of a p53 peptide in the transactivation domain.6 This class of compounds was called Nutlins. Unlike other previously discovered protein antagonists, due to their small molecular weight and high permeability, Nutlins can pass the membrane and elicit effects more efficiently.7 It was found that Nutlin compounds not only can stop the tumor progression but also shrink the existed cancer cells due to the elevated apoptosis effect elicited by prolonged p53 activity.7 Moreover, Nutlin might be considered relatively safe for the normal proliferated cells, such as human fibroblasts. This is because of that the cancer cells were found to be more sensitive to the activated p53 function than normal cells (Figure 4).7 In the usage of Nutlin combined with radiation therapy, it was indicated that the cell apoptosis induced by p53 might able to eliminate the side effects that were usually brought up by the radiation.7 However, there are many other types of normal human cell that are highly sensitive to p53 activities, which would greatly narrow down the therapeutic window of Nutlin.7 Also, since the effect of Nutlin could only inhibit the wild-type p53 and MDM2 complex, it would become useless in the tumor types that have mutated p53 proteins.6,7 Further clinical studies and experiments are still needed for investigating the side-effects of this class of antineoplastic agents.