Activation of p53 - The Tumour Suppressor for Cell Cycle Arrest and their role in Cancer

hi, gopal,The TP53 gene is one of the most studied genes in human cancer.
Gene therapy is considered to be the breakthrough in the 21st century in health sector.
----> Due to many advantages it provides like tumour specific activity, minimal side effects,etc p53 gene therapy has been some of the most researched topic in cancer treatment.
----> Clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies.
----> Progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are being reviewed.
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----> To clarify your doubt regarding the recent research in this field, i would like to put forth before you some facts:
1) p53-restoring gene therapy, an approach that earlier showed its promise in the work of Roth and co-workers78 almost 15 years ago, is now being evaluated as an adenoviral p53 gene therapy product, Advexin, in phase III clinical trials.
2) emergence of p53 isoforms are at the forefront of the p53 scene.
3) recent findings of the use of fat drop nano particle used as a vector for p53 gene delivery.
4) research work regarding the role of p53 in senescence and li fraumani syndrome.
5) p53 gene therapy in various cancers like oral, prostrate are being investigated and their effects in combination with radiation and chemotherapy.
These are just some of the recent research work going on..

Reference: http://www.nature.com/cgt/journal/v16/n1/full/cgt200869a.html

hi, some of the cancers caused due to mutations other than p53 are enlisted below:

Gene that is mutated
1) BRCA1 and BRCA2 gene.....................................Breast cancer
2) kinase gene (BRAF).......................................malignant melanoma
3) PDGFRA...................................................gastric cancer
4) TMPRSS2,ERG,Hras.........................................prostrate cancer
5) KRAS,CDKN2A..............................................pancreatic cancer
6) CTNNB1...................................................liver cancer
7) BRAF,NRAS................................................skin cancer

These are some of the cancers that are caused due to gene mutations other than p53. A detailed info on the cancer caused due to mutations can be obtained from the reference cited below.

Reference: http://www.sanger.ac.uk/genetics/CGP/cosmic/

hi, parth. Its good your hospital is moving towards these effective products. however you would have to wait for this product to get approved in india.
--- Benda Pharmaceutical, a China-based pharmaceutical company had announced that Gendicine, a recombinant human adenovirus vector p53 gene injection, for the treatment of cancer, had passed major milestones in its clinical trials in India and was expected to be approved for sale in 2008.
--- The company had entered into a joint venture with a leading Indian pharmaceutical firm (name releasable upon drug approval) to launch Gendicine([R]) in the Indian market.
--- However the approval has been delayed due to some unknown reasons, but its just a matter of time for it to enter the indian market and become available for the public welfare.

Reference : http://www.genetherapyreview.com/gene-therapy-blogs/viewpost/86.html

Mr. Roshan,
-- p53 is a short-lived protein that is maintained at low, often undetectable levels in normal cells . Tight regulation of p53 by MdM2 and Jnk which are p53 ubiquitin ligase causing degradation of p53 and negative regulation by binding to p53, maintain low p53 protein product in normal cells.

refernce: Lane, D., 1998, Nature, 394: 616; (Review p53 activation)

1) p53 proteins have been found to be of great prognostic value as a biomarker in many cancers as per recent clinical studies.
----> Introgen Therapeutics, Inc., reported results of its phase III trial of Advexin(r), a modified adenovirus that expresses the tumor-suppressing gene p53, for end-stage head and neck cancer.
The trial showed that p53 expression in the patient's tumor before treatment is a reliable biomarker for how to treat head and neck cancer.
----> In another trial, changes in expression of gene p53, and also its mutations, cause variations of cellular protein p53 concentration.
Higher cellular protein p53 levels are associated with increased protein transfer to the extracellular liquid and to blood. It has been observed that increased blood serum protein p53 concentrations may have a prognostic value in early diagnosis of lung cancer.

2)sir, if you are referring to the p53 gene therapy, Molecular modeling of protein structure has resulted in the rational design of peptides from proteins that control cell proliferation that appear to block the growth of cancer cells selectively.
----> p53-derived peptides induce tumor cell necrosis of many different types of human tumors and block the growth of a highly metastatic pancreatic tumor in nude mice. These peptides damage the cancer cell membrane but do not affect the membranes of untransformed cells.
----> Moreover,various p53 variants have been designed which show the same activity.The transcription factor p53 is normally regulated by a variety of post-translational modifications. The insertion of peptides into intrinsically unstructured domains of p53 generated variants that were activated up to 100-fold by novel effectors (proteases or antibodies).
----> thus, there has not been a problem with the structure variation.
hope i have given a satisfactory answer. thank you.

reference: 1) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2045634/
2) http://www.cancer-therapy.org/CT5B/HTML/38._Bowne_et_al,_331-346.html
3) http://www.springerlink.com/index/NJN7J16R6385531K.pdf

Thanks pankaj. your answers are as folllows:

1) P53 gene after the intratumour administration enters the cancer cells through adenovirus infection-mediated endocytosis . In normal cells , it remains inactivated as there is no DNA damage and the p53 gene doesnot express,while in cancer cells,as it senses DNA dmage, it gets activated and expresses the protein which perform its function.
Thus, the fact that p53 is activated by DNA damage helps it to differentiate between cancer and normal cell.

2) Different Strategies used for activation of p53 are:
-----> posttranslational modifications like acetylation,
-----> Mdm2 inhibition: Blocking p53-Mdm2 interaction is able to activate p53. Downregulation of mdm2 is brought about by Mdm2 antagonists,by antisense peptide nucleic acid conjugates, nutlins, etc.
-----> Nuclear export inhibitor: leptomycin B inhibits the nuclear exportin protein CRM1. The inhibition of export activates p53 dependent transcription.
-----> cdk inhibitor: Non-genotoxic activators of the p53 response include the cdk inhibitor Roscovitine. The R isomer (CYC202) of this compound is currently in clinical trial.
The link between transcription and signalling to p53 is currently the focus of intense study as it may represent a unifying principal in how the p53 pathway senses cellular stress that should invoke the p53 system.

3) No, there is no effect on the phyiological condition of normal cell function.
-----> Normally p53 is a very unstable protein and is present only in minute concentrations in the cell. Even these small amounts of p53 are not fully active as a transcription factor, because the negative regulator protein, Mdm2, binds them.
-----> When cells are exposed to a wide variety of aberrant growth signals, the p53 protein is activated and stabilized and triggers the expression of downstream genes such as p21 that trigger cell cycle arrest, or Puma that triggers apoptosis.
-----> By virtue of lack of DNA damage, exogenous p53 gene does not express in a normal cell, and therefore does no harm to it.

Reference: Prives, C., 1998, Cell, 95: 5-8; (Review p53 activation)

A Very good question, Mr. Ayush.
1) There are many advantages of p53 activation therapy over IGF-1 blockage therapy:
a) The p53 acts only on the cancer cells and has no harmful effects in the normal cells unlike IGF blockade therapy.
b) Administration of p53 doesnot cause much side effects except self-limiting Grade I and II fevers lasting approximately three hours.
-------Whereas, many of the hitherto developed IGF-1R TK inhibitors have caused substantial inhibition of the IR(insulin receptors). Such cross reaction would probably cause diabetic reactions in patients and can therefore not be accepted.
-------There is also possibility of cardiac toxicity.
c) Whereas, p53 product is already available in the market and benifitting the people, the methods currently available for targeting IGF-IR, are still not ideal for clinical applications.
d) Recently, there has been a finding that in patients having mutated p53, the IGF blockade therapy showed no effects. hence, P53 activation is necessary for this therapy.

2) The IGF blockade therapy mainly aims at apoptosis, hence both p53 activation and IGF blockade can cooperate to induce apoptosis in cancer cells.
--However, it has also been found that p53 represses the IR promoter and reduces the IGF circulating levels, and ineffectiveness of IGF blockade therapy in absence of activated p53.
--If the side effects with the IGF blockade therapy are successfully removed (like selective action on IGF and no effect on insulin receptors), then the combination can be fruitful instead of p53 activation therapy alone.
--Thus, the combination can be a future strategy in the cancer treatment and much research needs to be done towards this.

reference: 1) CANCER GENE THERAPY:FRINGE OR CUTTING EDGE?
NATURE REVIEWS | CANCER, VOLUME 1 | NOVEMBER 2001
2)http://www.pharmastrategyblog.com/2009/06/igf1r-inhibitors-in-cancer.html

There is only one approved P53 product in the market i.e Gendicine.
-------The first gene therapy virus approved for clinical use in China (2003), Gendicine™ (from Chinese Shenzhen SiBiono Genetechnologies) is a p53 adenovirus for the treatment of head- and neck squamous cell cancer in combination with radiotherapy .
-------Gendicine is a gene therapy drug to treat malignant cancers. It is mainly composed of replication-incompetent recombinant Ad-p53 virus particles, which based on adenovirus serotype 5 and human wild-type p53 tumor suppressor gene.
------- A Gendicine vial contains 1 x 1012 viral particles in 1 mL of WFI (water for injection) buffered with Tris (made by Amresc) and glycerol.
------- In clinical trials, Gendicine has been used to successfully treat cancers of the digestive tract (esophageal, gastric, intestine, liver, pancreas, gallbladder, rectum), lung cancer, sarcoma, thyroidgland cancer, breast cancer, cervical cancer, and ovarian cancer.
-------Although Gendicine has not been formally approved by SFDA for indications other than HNSCC, terminal patients with no other avenue of treatment have been allowed, on a case-by-case basis, to receive Gendicine with permission from the SFDA.

A similar product: Advexin™ (INGN 201; Introgen; Austin, TX, USA) is pending approval from EMEA.
--> ADVEXIN is considered an 'Orphan Drug' in the U.S. for the treatment of recurrent, refractory head and neck cancer, which, if approved, entitles the drug to extended market exclusivity for the approved indication.
--> Many products are in phase 2 and phase 3 clinical trials, so they may arrive in the market in the coming years.

Reference: http://www.echinabio.com/service/service.aspx?serviceid=276
http://www.prnewswire.co.uk/cgi/news/release?id=186332

thanks kinjal for your comment.
---> p53 gene therapy can be used in cancer along with combination of chemotherapy and radiation therapy.It would allow physicians to use a lower dose of therapies, achieving the same or enhanced therapeutic results but sharply diminishing the side effects so troublesome in many treatments.

---> Two adenoviral gene therapy products have now been approved for clinical use in China, and elsewhere at least four products are in phase III clinical trials.
---> The adenovirus vector is the most commonly used vector for clinical gene therapy due to its high rate of gene transfer in vivo. However, the clinical efficacy of this vector has yet to be proven, despite over 300 clinical trials that have shown it to be well-tolerated and efficient in gene transfer.

---> Recent studies in China have reported improved efficacy of an adenoviral gene therapy product in combination with radiotherapy and/or chemotherapy for the treatment of several types of cancer.

---> There are now at least three phase III clinical trials for adenoviral cancer gene therapy that are ongoing in the U.S., and two of these call for combination therapy with either chemotherapy or radiation.
---> In addition, in the European Union, one adenoviral gene therapy product for malignant glioma in combination with surgery showed a therapeutic benefit in the preliminary results of a phase III trial.

---> A recombinant p53-based gene therapy (p53-Adv) is now in phase 3 clinical trials in patients with cancer.
ADVEXIN has demonstrated increased survival and durable tumor growth control in recurrent head and neck cancer patients. ADVEXIN has demonstrated clinical activity in a number of solid tumor types in multiple phase 1, 2 and 3 clinical trials conducted worldwide.
---> A request for accelerated approval for ADVEXIN is now pending at the FDA. The FDA has selected ADVEXIN for its fast track program to fill an unmet medical need and has designated ADVEXIN for orphan drug use for recurrent head and neck cancer.

---> The wealth of clinical data available on adenoviral-p53 gene transfer in cancer patients led to the approval of one such product, Gendicine, for use in SCHNN by the Chinese State FDA in 2003.
---> Moreover, Many clinical trials are in phase 2 for other carriers of p53 like nano particles.

Reference: 1) http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summar...
2) http://www.medscape.com/viewarticle/480728_4

Hi bhavna, i have covered the detailed explanations of the functions in the slides itself, but to clarify your doubts, i would like to give some details.
P53 has many functions, the main ones are:
1) cell cycle arrest
2) apoptosis
3) DNA repair

The main function is to prevent the cells with DNA damage from going through the cell cycle.
---> Due to DNA damage, activation of P53 occurs which causes the cell cycle arrest. During this time,it repairs the damaged DNA.
---> If MINOR damage,then P53 repairs the DNA,
---> If Major damage, then P53 causes the cell to undergo apoptosis(cell death).

---> P53 binds in sequence specific manner to sites in certain genes (P53 target genes) such as WAF1, BAX, MdM2,etc as a transcription factor.
The resulting proteins perform the functions of cell cycle arrest, apoptosis and DNA repair.

---> P53 arrests the cell cycle primarily by up regulating p21 (Cip1/Waf-1), which inactivates CDK/cyclin.
Involvement of cyclins ensure successful transitions from S phase to G1.
---> Since p21 (cyclin dependent kinasre inhibitor-p21) inhibits CDKs, it results in inhibition of both G1 to S and G2 to mitotic transitions. (refer the figures in the presentation for better understanding)

---> In apoptosis, there are two pathways: Death receptor Pathway and Mitochondrial Pathway.
P53 protein mainly regulates the Mitochondrial Pathway.
---> P53 protein starts a pathway that releases cyt c from mitochondria.
This cytochrome c complexes with protein Apaf-1 and together they activate capsase 9.
---> The effector caspases (e.g caspase 3) start a pathway that results in cleavage of cell constituents : DNA, cytoskeletal components, enzymes,etc.
---> Later phagocytosis of these remaining components by macrophages mark the end of apoptosis.

AS IT MAINTAINS THE INTEGRITY OF THE GENOME, IT IS CALLED " GUARDIAN OF THE GENOME".

---> Moreover, recently its role in alzheimers as a biomarker and in Micro RNA processing( which control production of proteins invovled in cell prolifertion) has also been found out.
Hope the explanation clarifies your doubts.

Reference: 1) http://www.springerlink.com/content/j28v7m321t5288u3/

Hi Komal,thanks for your comment.

Yes, there are other 174 tumour suppressor genes. I would like to classify some of them according to their functions, so that you get the idea how they exert their actions.

1) Cell Cycle Inhibitors:
--->Rb gene (Retinoblastoma gene) mutation is involved in the cancerous tumour of retina.
The Rb protein prevents cells from entering S phase of the cell cycle. It does this by binding to a transcription factor called E2F.
This prevents E2F from binding to the promoters of such proto-oncogenes as c-myc and c-fos. Transcription of c-myc and c-fos is needed for mitosis so blocking the transcription factor needed to turn on these genes prevents cell division.

--->INK-4 Gene : Associated with various cancers. It produces P-16 that inhibits Cdk4/Cyclin D action which is necessary for cell cycle transition.

2) Repressor Transcription Factors:
---> WT1 is a repressor that suppress transcription factor (Insulin like Growth Factor) which will contribute in the development of tumour.
---> MEN1 also suppresses transcription factors and its mutation is involved in Multiple endocrine neoplasia type 1

3) Activator Transcription Factors:
---> SMAD Family that is activated by TGF-B, leading to inhibition of cell proliferation. Other TS genes in this class are BRCA1,BRCA2 that activate the transcription factors for DNA DAMGAE REPAIR.

4) Others:
---> CAP1,101F6,DCC involved in apoptosis; NF1,NF2 regulating RAS GTPase invoved in neurofibromatosis; Cep63, which patrols the cell’s centrosomes – the molecular machines that control the distribution of DNA when a cell divides,etc.

Reference: http://www.cise.ufl.edu/~yy1/HTML-TSGDB/Homepage.html
http://themedicalbiochemistrypage.org/tumor-suppressors.html

Very Good questions, Dr. Murthy. The answers to your questions requires some basic concepts to be clarified. So,the answers are as follows:

1) DNA substitution mutations are of two types: Transition and Transversion.
--> Transitions: interchanges of purine (A G) or of pyrimidine (C T)
--> Transversions: interchanges between purine and pyrimidine bases.

-------A predominance of GC->AT transition at the CpG nucleotide ( colon, ovary, brain or leukemia) is the consequence of spontatneous deamination of 5-methylcytosine.
-------The cytosines in CpG nucleotides of the P53 gene are methylated in normal tissue. Cytosines are vulnerable to deamination and 5-methylcytosine on deamination forms THYMIDINE.
-------Thymidine(T) cannot be processed by the enzyme URACIL GLYCOSYLASE which removes URACIl(U) formed by the deamination of unmethylated cytosine.
-------Thus Due to the vulnerability of cytosine to undergo deamination, CpG nucleotide mutates at a high rate.

--> A High frequency of GC->TA Transversions ( Lung, Head and Neck) is strongly indicative of exposure to EXOGENOUS CARCINOGENS such as polycyclic aromatic hydrocarbons (PAHs).
--> These important environmental chemical carcinogens are formed when organic material is burnt incompletely, and they are present widely in the environment in, for e.g, cigarette smoke, coke oven fumes and engine exhaust.

--> EXOGENOUS MUTAGENS like BPDE or UV light have a greater affinity for methylated CpG nucleotides,thus causing mutation.
-------Benzopyrene(BP) is a potent mutagen that is released in ciggarette smoke from tars in tobacco. The lung epithelial cell absorbs BP and converts it to Benzopyrene Diol Epoxide (BPDE) and this by binding to p53 causes mutation.

--> ENDOGENOUS MUTAGENS, derived from an altered cell metabolism could also target methylated CpG nucleotide leading to transitions.

--> INHERITED MUTATIONS are also observed as in Li- Fraumeni syndrome, where 70% of the families inherit a mutation of P53.

--> Thus, mainly EXOGENOUS CARCINOGENS like BPDE, UV light, ENDOGENOUS MUTAGENS and INHERITED MUTATIONS are the main CAUSES of MUTATION of P53.

2) The depressors of p53 include :
a) MdM2 protein : It is the product of an oncogene amplified in several tumours, including in particular sarcomas. By binding to p53, mdm2 not only earmarks the protein for degradation but also conceals transcription activation domain and mediates p53 export from the nucleus into the cytoplasm.

b) JNK (c-Jun N-terminal Kinase) : Inactive JNK binds to residues 97-116 in p53 and targets p53 for degradation by the proteasome.

c) DNA tumour viruses : E6 oncoprotein in Human Papillomavirus, Adenovirus E1B 55K protein, SV40 large T antigen, etc are some of the depressors of p53.

3) The identification and characterization of the p53 protein has relied extensively on immunological methods, including IMMUNOHISTOCHEMISTRY and IMMUNOBLOTTING.

--> p53 immunohistochemistry has been used to study the p53 protein in urothelial carcinomas and dysplasias, in lymphatic malignancies and in prostatic, lung and breast carcinomas .
--> p53 is constitutively repressed in most tissues and is thus almost undetectable by immunological methods in normal cells.
--> It can, however, be detected in a variety of tumours and transformed cells because of the extended half-life of the wild-type or mutated-type protein.
--> Immunoblotting is widely used for studies on p53 and has been called “the gold standard for demonstration of p53 expression”.

How it works??
------The extension of the half life of MUTATNT P53 results in a sufficient increase in the amount of intracellular protein for it to become immunohistochemically detectable.
------Thus,higher cellular levels of proteins and distribution in cytoplasm provide parameters by which mutation of genes can be detected.
------A variety of antibodies have been developed for immunological detection of p53. The monoclonal PAb240 antibody detects both mutated and wild-type proteins under denaturing conditions, e.g. in immunoblotting.
------Staining methods are used here.

-->Moreover many PRE SCREENING methods have been developed to increase the sensitivity of detection of mutations. They are:
i) SSCP.....................Single Strand Conformation Polymerisation
ii) DGGE.....................Denaturing gradient gel electrophoresis.
iii) Yeast Assay
iv) dHPLC....................denaturing High Performance Liquid Chromatography
v) Others...................Cleavase,RNA protection,etc

reference: 1) http://herkules.oulu.fi/isbn9514270398/html/c182.html
2) the p53 mutation handbook 2.0 available online http://P53.free.fr
3) http://cancerres.aacrjournals.org/cgi/content/abstract/51/21/5976

A DNA tumour virus is a virus that contains a DNA genome and can cause tumours.
e.g papillomavirus,polyoma virus, adenovirus, etc.

= DNA tumor viruses carry oncogenes (e.g. SV40 T-antigen) which are true viral genes with no cellular homologs.
= These viruses integrate their genome into the host cell and cause transformation that may result into loss of growth control, interference with growth receptors,etc.

= The region of the viral genome (DNA in DNA tumor-viruses) that can cause a tumor is called an oncogene. This foreign gene can be carried into a cell by the virus and cause the host cell to take on new properties.

= The virus mimics mutation and takes the tumor suppressor out of action by complexing it in an inactive form that cannot bind to the specific site on DNA. In the case of a human papilloma virus-infected cell, p53 is bound by the E6 protein and directed to a protease that recognizes a cleavage site in p53, thereby destroying it.

= I would like to give a simple example:
DNA virus like adenovirus and SV40 have early and late functions. early functions are involved with expression of proteins involved in viral DNA replication. late functions are involved in the expression of viral structural proteins that combine to form the mature virus on or after replication.
SV40 expresses two such proteins, the T antigens (large T and small T antigen).SV40 large T antigen can bind directly to the tumour suppressor proteins and inactivate them, thereby inducing the cell to go from Go to S phase.
Thus, some of the DNA tumour viruses cause cancer by interaction with TS genes, although other mechanisms are also present.

= Refernce: 1) http://pathmicro.med.sc.edu/lecture/RETRO.HTM

2) http://www.salk.edu/pdf/faculty/oshea_cogd_review.pd

no sir, p53 is not the only one regulating apoptosis.
other factors that regulate apoptosis are:
1) death domain proteins : there are 2 pathways for p53 activation. one is the mitochondrial pathway where p53 plays an important role. other one is the death receptor pathway where stimulation of death receptors are involved.
2) caspases
3) bcl2 family proteins which have both anti apoptotic and pro apoptotic genes
4) protein kinases/phosphatases
5) TNFR family(tumour necrosis factor receptor), etc

thanks for your comments
Generally, any sort of DNA damage causes p53 activation.some of the factors causing DNA damage are UV radiation, hypoxia, activated oncogenes,etc.
It has been found that even a small transformation in DNA causes the p53 level to elevate.
DNA damage causes post translational modifications in the C terminal of p53 and thus causes its activation.

In fact Mdm2 is the main regulator of p53 and is involved in a negative feedback loop.
Other alternate mechanisms have been proposed but they are not so well established. Many proteins able to interact with p53 may also play a role in p53 regulation.

some of the regulators are:
1) JNK:
JNK, the c-Jun N-terminal Kinase, plays two distinct roles in the control of p53 activity. When inactive, this kinase binds to residues 97-116 in p53 and targets p53 for degradation by the proteasome. In contrast, active JNK phosphorylates p53 on threonine 81 and participates in its activation.
Activation of p53 by these agents is prevented by a peptide blocking p53-JNK interaction. However, the contribution of the JNK pathway to p53 activation in response to genotoxic stress is still poorly understood.

2)Poly(ADP-ribose)polymerase :
PARP is known to be involved in the regulation of p53, although the relationship is not clear. There are studies showing that PARP upregulates p53.
Mice deficient in the PARP-1 gene (encoding poly-ADP ribose polymerase) show low levels of p53 accumulation in response to IR.
PARP-1 is rapidly activated after IR and is involved in the recruitment of DNA repair enzymes at the site of the lesion.
On the other hand, contradictory results have also been published. X-ray-induced p53 accumulation was prolonged in mouse prostate cells treated with a PARP inhibitor 3AB .
Altogether, the relationship between PARP and p53 seems to differ in different models and still needs further studies to be thoroughly understood.

3)p14ARF protein (ARF, Alternative Reading Frame):
The p14ARF protein binds MDM2 protein, and inhibits the E3 activity of MDM2, in addition to sequestering MDM2 into the nucleolus. Consequently, p14ARF disrupts the negative feedback inhibition of p53 by the binding to MDM2.
Recent results indicate that activation of the p14arf-p53 pathway can suppress the transformation of primary epithelial cells in vitro.

4)Oncogenic Ras:
Ras is capable of inducing p14ARF expression which in turn inhibits Mdm2. It could also increase the levels of Mdm2, through increased Mdm2 transcription, thereby limiting availability of p53 . The mechanism that underlies the balance between the two pathways requires further investigation.

Presently certain uncertainties prevail over the exact role of these regulators. These p53 regulators are the topic of research presently and they could play an important role in the cancer therapy.

Mdm2 is generally considered as the universal regulator of p53.
The p53–Mdm2 paradigm represents the best-studied relationship between a tumor suppressor gene which functions as a transcription factor and an oncogene, which functions primarily as an E3 protein ligase.

reference: http://herkules.oulu.fi/isbn9514270398/html/x243.html