2012 Group 9 Project

From CellBiology

p53 Signalling Pathway


Cartoon representation of a complex between DNA and the protein p53. The orange structure is DNA, and p53 is purple/blue.

Through regulation of the cell cycle, the p53 gene plays an important role in suppressing tumour formation [1] . The p53 protein is tightly regulated in cells and responds to stress signals produced by DNA damage, oncogenic gene expression and anoxia [1][2]. It controls the activation of apoptosis or cell cycle arrest in response to damage, therefore maintaining integrity of the genome. [2]. p53, also known as a tumour suppressor gene, is one of the main sentinel transcription factors that prevents cells from accumulating DNA damage and eventually perpetuate malignancy [3].

P53 loses its ability to regulate cell growth when functional inactivation occurs. This may happen through gene mutation and deletion, protein degradation, or viral oncogene binding causing the mammalian cell to become susceptible to oncogenic stimuli and environmental insults. This subsequently leads to growth deregulation and malignant progression [4]. There are many mechanisms that suggest P53's protective element against malignant cells, but in recent years more studies has proven that P53 integrates signals from the cell's internal and external environment[4]. These signals are used to respond to inappropriate growth promoting or growth inhibiting conditions [4]. Consequently, mutation or loss of p53 results in genomic instability that promotes risk and facilitates progression of tumours, and for that reason it is the most frequent genetic mutation in human tumours [1].

This page will discuss the history of the p53 signalling pathway, receptors and proteins involved in the pathway, the steps involved in the pathway, normal and abnormal functions of the pathway, finishing with current research and possible future directions for this crucial cellular signalling pathway.

p53-DNA Complex


1979: p53 was first discussed in studies on the SV40 virus by Lane and Crawford[5] and Linzer and Levine[6].
1982-83: The TP53 gene was first cloned at the Russian Academy of Sciences by Chumakov, Iotsova and Georgiev[7], followed by further cloning of the human tumour antigen p53 in mice by Oren and Levine[8].
1984: Cloned p53s were tested for oncogenic features in normal embryonic cells by Eliyahu et al[9] and in Ab-MuLV-transformed cell lines by Wolf, Harris, and Rotter[10]. Wolf and Rotter were able to inactivate p53 in tumor cells in two separate studies, one of which was in leukaemia [11][12]. Maltzman and Czyzyk established that p53 was reactive to UV radiation in mice [13].
1988: The murine wild-type p53 sequence was confirmed by Finlay et al[14] and Eliyahu et al[15].
1989: Baker et al show that p53 has tumor suppressor gene characteristics, rather than oncogenic, and is assumed a tumor suppressor gene in colorectal cancer[16].
1990: p53 germline mutations (those that occur during meiosis) are found in Li-Fraumeni syndrome by Srivastava et al[17]. Cell proliferation studies by Mercer et al[18] and Michalovitz, Halevy, and Oren[19] show that p53 stimulates termination of mitotic cell cycle. p53 is found to be a transcription factor (sequence-specific DNA-binding factor) in vitro by multiple research teams across the globe.[20][21][22][23].
1991: Yonish-Rouach et al show that wild-type p53 induces apoptosis in leukaemia cells[24] and Shaw et al find similar results but in human colon tumor-derived cell lines[25].
1992: Momand et al prove that the oncogene MDM2 acts as a negative regulator, preventing transcription[26]. p53 knock-out mice are found to be more susceptible to cancer in a study by Donehower et al[27]. p53 appears to conserve genome stability via cell cycle control and gene amplification in studies by Livingstone et al[28] and Yin et al[29].
1993: The p53/MDM2 feedback loop is established by Wu et al[30] and p21 is described as a potential mediator of p53 tumor suppression by el-Deiry[31]. p53 is voted ‘Molecule of the Year’ by Science magazine[32].
1994: The first p53-DNA complex crystal structure is described in a research article by Cho et al in order to understand tumorigenic mutations[33].
1997: MDM2 is found to prompt p53 ubiquitination and degradation by Haupt et al[34] and Honda, Tanaka, and Yasuda[35]. p63 and p73 are outlined [36][37]. An association between ARF and p53 is made by Kamijo et al[38]. Serrano et al find that p53 compromises senescence[39].
1998: In response to DNA damage, ATM phosphorylates p53[40].
2000-2001: p53 is cloned in Drosophila by Ollmann et al[41] and C. elegans by Derry, Putzke, and Rothman[42].
2002: p53’s role in organismal aging is established by Tyner et al[43].
2003: Apoptosis is induced via p53 acting on mitochondria in a study by Mihara et al[44].
2004: Bond et al discover that MDM2 polymorphism hastens cancer cell proliferation[45]. Small-molecule antagonists of MDM2 are believed to activate the p53 pathway in cancer cells[46]. p53 gene therapy is approved in China[47].
2005: Multiple isoforms of p53 are identified for research purposes by Bourdon et al[48]. p53’s role as an antioxidant is discovered by Sablina et al[49] and p53 is found to regulate metabolism via AMP-activated protein kinase[50].
2007: p53’s importance in reproduction is revealed by Hu et al as it is required for embryo implantation [51]. p53-induced senescence defends against cancer in vivo [52][53] and p53 is found to modulate miRNA expression by He et al[54]. p53 is found to inhibit the IGF-1/mTOR pathway[55].
2008: Small molecule p53 activators are discovered by Lain et al in vivo with potential for therapeutic interest[56].
2010: New approaches to cancer drug discovery as structures of inhibitors of MDM2 and MDMX are revealed by Popowicz et al[57]

Recent developments (2010-2012) in the subject of p53 pathway are described in the Current Research section.


Different gene expression in p53 signalling pathway

The p53 network is normally ‘off’. It is activated only when cells are stressed or damaged such cells pose a threat to the organism: they are more likely than undamaged cells to contain mutations and exhibit abnormal cellcycle control, and present a greater risk of becoming cancerous. The p53 protein shuts down the multiplication of stressed cells, inhibiting progress through the cell cycle. In many cases it even causes the programmed death (apoptosis) of the cells in a desperate attempt to contain the damage and protect the organism. The p53 protein therefore provides a critical brake on tumour development, explaining why it is so often mutated (and thereby inactivated) in cancers[58].

DNA damage acts as an activating ‘on’ switch. A single break in a double-stranded DNA molecule may be sufficient to trigger a rise in levels of p53 protein. This remarkable sensitivity to DNA damage confounded subsequent studies that sought to establish whether the p53 response could be triggered by other signals[31]. It was difficult to show that these other signals did not cause at least a few breaks in double-stranded DNA. Recent research, however, has confirmed the existence of at least three independent pathways by which the p53 network can be activated.

One pathway is indeed triggered by DNA damage, such as that caused by ionizing radiation. Here the activation of the network is dependent on two protein kinases — enzymes that add phosphate groups to other proteins. Two of the major kinases in question are called ATM (for ataxia telangiectasia mutated, named after a disease in which this enzyme is mutated) and Chk2. ATM is stimulated by double-strand breaks, and Chk2 is in turn stimulated by ATM[59].

The second pathway is triggered by aberrant growth signals, such as those resulting from the expression of the oncogenes Ras or Myc. In this case, activation of the p53 network in humans depends on a protein called p14ARF[60].

The third pathway is induced by a wide range of chemotherapeutic drugs, ultraviolet light, and protein-kinase inhibitors. This pathway is distinguished from the others because it is not dependent on intact ATM, Chk2 or p14ARF genes, and may instead involve kinases called ATR (ataxia telangiectasia related) and casein kinase II.

All three pathways inhibit the degradation of p53 protein, thus stabilizing p53 at a high concentration. The increased concentration of p53 which is covalently modified allows the protein to carry out its major function: to bind to particular DNA sequences and activate the expression (transcription) of adjacent genes. These genes, directly or indirectly, lead ultimately to cell death or the inhibition of cell division[59].


From the P53 signalling pathway diagram, we can see that there is a number of proteins are involved directly or indirectly in the pathway leading to P53 mutation. However we have chosen to focus on 3 of the proteins that are involved in the cascade that can trigger P53 mutation which are ATM, Chk2 and P14arf.


Human p53 is a nuclear phosphoprotein of molecular weight 53 kDa, encoded by a 20-Kb gene containing 11 exons and 10 introns, which is located on the small arm of chromosome 17. It contains 393 amino acids and comprised of several structural and functional domains. For example, there is a N-terminus domain and a proline rich region. The proline-rich region plays a role in p53 stability regulated by MDM2, where in p53 becomes more susceptible to degradation by MDM2 if this region is deleted [61].

ATM and Chk2

Ataxia telangiectasia mutated (ATM) gene is a protein that plays a critical role in sensing DNA double strand breaks in mammalian DNA. It plays a critical role in activating appropriate damage response pathways leading to either cycle arrest or apoptosis [62].

Chk2 is also a protein kinase that is activated in response to cell damage. It is located on chromosome 22, specifically at the long arm of the chromosome. ATM gene is required to activate Chk2, so it is assumed that ATM and Chk2 works in a linear pathway to the activation of P53 pathways[62].


P14arf is a gene that inhibits mdm2 function. It is located in chromosome 9 on locus 21. Loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in mdm2 and, therefore, loss of p53 function and cell cycle control [63]. p14arf is a tumour suppressor protein that bind to the MDM2-P53 complex and prevents degradation of the P53[64] .


Estrogen Receptor alpha (ERa) was found in more than 70% breast cancer cells [65]. Liu, Schwartz, and Brooks [66]had earlier found out that ERa binds to p53 protein. The experiment involves p53, ERa, and MDM2. p53 upregulates MDM2 production and MDM2 inhibits p53 transactivity and p53 protein production via ubiquitin-proteosome pathway. ERa on the other hand, binds to the p53-MDM2 complex, forming a ternary complex. The role of ERa is to protect p53 from being suppressed and deactivated by MDM2. This could be the mechanism utilized by the anti-estrogen drugs such as tamoxifen to treat breast cancer [65]

Normal Function

student drawn image representing p53 function.

P53 has a principal role in acting as a transcription factor to promote a range of functions that are critical in maintaining celllular integrity throughout proliferation [6]. Due to the multifunctional nature of the p53 protein, phosphorylation of the gene may be followed by differential responses [60]. However, apart from its main role in tumour suppression, p53 has recently been found to have a wider range of functions including those in cell membrane function and adhesion, DNA repair, cellular metabolism and motility [6]. In reply to stress signals and DNA damage, p53 upregulates gene expression to bring about protective mechanisms including cell cycle arrest, DNA repair, senescence or apoptosis [67].

DNA Damage

The DNA-damage pathway is initiated by 2 associated protein kinases, ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated related (ATR). These protein kinases activate analogous down-stream pathways in response to DNA damage, however the types of damage sensed by each ATM and ATR are different [2]. Upon activation by DNA stress signals, they phosphorylate various targets including p53 to initiate cell cycle arrest, and stimulate DNA repair pathways through the phosphorylation of DNA repair proteins [2]. However, when phosphorylated, p53 induces Murine Double Minute 2 (MDM2) - an E3 ubiquitin ligase - to catalyze its degradation [68]. MDM2 therefore works as an antagonist against p53 function [68]. And as a result, the p53-MDM2 complex requires disruption in order for p53 to escape the effects of MDM2, maintain stabilization, and initiate its biological response [68].

Cell Cycle Arrest

Cell cycle arrest happens in the late G1 phase of the cell cycle and is induced by p53-mediated transcription of CDK1A (p21) gene [2]. The CDKN1A gene binds to CDK2 and CDK4 to inhibit their activity, which effectively stops the cell cycle to allow time for DNA repair[60] . Initiation of cell cycle arrest occurs through the inhibition of cyclin-CDK complexes as well as prevention of RB (retinoblastoma) gene phosphorylation, the latter of which is functionally required for cellular entry into G1 phase [2].

DNA Repair

p53 targets transcription of certain mechanisms and proteins including Growth arrest and DNA damage Inducible 45 (GADD45) and Proliferating Cell Nuclear Antigen (PCNA) in order to stimulate DNA repair [2][60]. Successful damage repair results in p53-initiated up-regulation of MDM2 which leads to p53 destruction and hence an end to cell cycle arrest [2]. If repair does not occur, apoptosis or senescence may be initiated by p53 instead.


Senescence is referred to as a cell permanently in irreversible cell cycle arrest [2]. It is a mechanism of tumour suppression which becomes activated as a response toward cellular insults including DNA damage and oncogenic signals [69]. It is distinguished by particular differences in gene expression and morphological characteristics [2]. It is dissimilar to the reversible form of cell cycle arrest or quiescent cells in the G0 phase of the cell cycle [2]. Senescence induction requires p53 or RB gene activation as well as expression of Cyclin-dependant kinase inhibitors (CDKIs) or other mediators[2]. The degree of p53 involvement in its initiation however, varies depending on cellular context and type of activating insult [69].


The pro-apoptotic pathway is the essential mechanism of protection against irreversible DNA damage and therefore effectively also against neoplasia(1). The induction of programmed cell death occurs in response to cellular aberration, including oncogenic stress, hence making it a crucial function in tumour suppression [59].Other cellular stress signals including interleukin-3 deprivation for example, may also induce apoptosis [59]. In response to stress signals, p53 is not degraded and therefore accumulates and binds to specific target sites of chromatin to initiate the apoptotic pathway [6]. Transcriptional activation of pro-apoptotic Bcl-2 genes is initiated by p53 at the sites of binding in chromatin [6]. The Bcl-2 genes which include BAX, Bbc3 PUMA and NOXA, are upregulated to mediate normal apoptotic function[59]. Jabbour et al. (2012) also state that in abnormal p53 function, it is not solely apoptotic failure that contributes to oncogenic potential, but depending on the cell and tumour type, p53-initiated apoptosis may promote tumour development [59]. For example, as suggested by Jabbour et al. (2012), T-cell lymphoma caused by irradiation requires a certain amount of cell death initiated by p53, in order to create a niche environment that encourages proliferation of the malignant cells [59].

Abnormal Function

The role of p53 in the progression from adenoma to carcinoma in colorectal cancer

Molecular action of p53 in carcinogenesis

According to a study in 2005 by Munro, Lain, and Lane [70] the relationship between abnormality in p53 gene and tumour progression is yet to be adequately understood, even though more than 50% p53 mutations was identified among colorectal cancer patients. p53 is a tumour suppressor gene and it requires both genes on both allele to be switched off for phenotypical pathologic event to occur [71].

G1 Cell Cycle Arrest

Cell lines with damaged p53 mechanism have been found as unable to activate p21 pathway (CDK-1 inhibitor) and the essential cell cycle arrest at G1 to allow DNA repair process to occur. Since the p21 pathway has been ineffective, the accumulation of DNA damages would then lead to multiple mutations and hence causes neoplasticity. The changes in a number of genes predisposes the cell to tumourigenesis and disease progression [71].

Oncogenic Amplification

The genetic instability imposed by p53 malfunction could result in neoplasticity such as the amplification of erbB2 oncogene, chromosome 17 allele loss,and some clonal chromosomal abnormalities. p53 abnormalities was found in mammary gland carcinoma in situ, suggesting abnormal p53 role in the evolution of carcinoma in situ to a more invasive tumour. The erbB2 oncogene was not found in in situ lesions but rather in invasive carcinomas [71].

Li-Fraumeni Syndrome

It was understood earlier in the earlier part of this page that both chromosomal copies containing the p53 gene need to be "switched off" in order for mutations to occur and other genetic pathological lesion to accumulate initiating tumorigenesis and becoming neoplastic. Li-Fraumeni Syndrome (LFS), is a very rare autosomal dominant disease caused by mutation of the p53 gene on chromosome 17. The heterogeneity of the disease suggest that the mutation only affect one gene of the paired allele. This further suggest that individuals born with this autosomal dominant disorder are highly susceptible to tumorigenesis [72]

LFS has high penetrance among individuals given that the DNA only require one p53 mutation on the other allele to allow DNA damage to accumulate. The mutation of the other p53 gene could be caused by external factors ("de novo") leading to suppression of both tumour suppressor genes. The most common malignancies developed by patients with LFS are osteosarcoma, malignant breast neoplasm, and cancer of the adrenal cortex [72].

In 2001 Gu, Kawai, Wiederschain, and Yuan [73] was studying the pathway abnormality among LFS-mutant p53 gene at molecular levels. They found that the mutant p53 gene was not only resistant towards degradation mechanism by MDM2 but did not manifest sufficient response towards DNA damage. The mutant p53 was ineffective in tumour suppression and was unable to cease cell cycle or trigger apoptosis. The mutant p53 had decreased affinity towards importin, which rendered the gene unable to pack and deliver the p53 protein to the nucleus for DNA repair processes [73].

Current Research

Current research on the p53 signalling pathway focuses on the development of anti-cancer treatments. Some hypothesis's also suggest other roles of p53 function, but have not been proved.

p53's Role in Aging

Dr Salvador Macip of the Department of Biochemistry University in Leicester is currently researching p53’s possible role in the body’s aging process. Although not published in any journals to date, his research has been presented in lectures and has some interesting theory behind it.

Macip’s Lecture Intro |Salvador Macip's Research Interests

Molecule Chaperones

In 2011, Hagn, Lagleder, Retzlaff, Rohrberg, Demmer, Richter, Buchner and Kessler from the Department of Chemistry of the TU Muenchen (Munich), highlighted the importance of other proteins in reinforcing the longevity of the p53 molecule, in particular heat shock protein 90 (Hsp90). [74]. With this information, researchers may be able to develop drugs or therapy that work on ‘chaperoning’ p53 when most needed, that is, in the presence of tumor development and even before tumor development in order to prevent it.

Nanoparticle-mediated p53 gene therapy

Very recent research by a team of pharmaceutical scientists in the US has shown great potential for the inhibition of tumor angiogenesis and growth. Prabha, Sharma and Labhasetwar (2012) utilised nanoparticle-mediated p53 gene therapy in mice to re-establish wild-type p53 functions in cancer cells. [75] In vivo, animals demonstrated survival rates and decelerate cancer progression. This is an example of p53 gene therapy where the nanoparticles established sustained transgenic expression, reducing development of new blood vessels (angiogenesis), and increased level of apoptosis among neoplastic cells. The potential of the nanoparticles could be extended for the use treating cancer in human patients.

Glossary of Terms

Angiogenesis: Growth of new blood vessels by sprouting from existing ones.

Anoxia: a condition characterized by an absence of oxygen supply to an organ or a tissue

Apoptosis: Form of cell death, also known as programmed cell death, in which a ‘suicide’ program is activated within the cell, leading to fragmentation of the DNA, shrinkage of the cytoplasm, membrane changes and cell death without lysis or damage to neighboring cells. It is a normal phenomenon, occurring frequently in a multicellular organism.

ARF: ADP Ribosylation Factor (ARF) is a member of the GTP-binding proteins responsible for regulating both COPI coat assembly and clathrin coat assembly at Golgi membranes.

ATM: a protein that regulates several cellular responses to DNA breaks.

C. elegans: Caenorhabditis elegans is a nematode (unsegmented) worm with very simple anatomy.

Chaperone (molecular chaperone): Protein that helps other proteins avoid misfolding pathways that produce inactive or aggregated polypeptides.

Drosophila: Species of small fly, commonly called a fruit fly, much used in genetic studies of development.

Gene therapy: The correction of a genetic deficiency in a cell by the addition of new DNA and its insertion into the genome.

Genome: The totality of genetic information belonging to a cell or an organism; in particular, the DNA that carries this information.

Germline mutation: present constitutionally in an individual (ie, in all cells of the body) as opposed to somatic mutations, which affect only a proportion of cells.

Heat shock protein (stress-response protein): Protein synthesized in increased amounts in response to an elevated temperature or other stressful treatment, and which usually helps the cell to survive the stress.

IGF-1/mTOR pathway: sense the availability of nutrients and mitogens and respond by signaling for cell growth and division.

In vivo: In an intact cell or organism.

Ionizing radiation: High-energy radiation capable of producing ionization in substances through which it passes. It includes nonparticulate radiation, such as x-rays, and radiation produced by energetic charged particles, such as alpha and beta rays, and by neutrons, as from a nuclear reaction.

Li-Fraumeni syndrome: A rare, inherited predisposition to multiple cancers, caused by an alteration in the p53 tumor suppressor gene.

Phosphorylation: Biochemical process involving adding a phosphate group to an organic compound.

Malignant: Describes tumors and tumor cells that are invasive and/or able to undergo metasis. A malignant tumor is a cancer.

MDM2: a protein that normally inhibits the ability of p53 to restrain the cell cycle or kill the cell, is overexpressed in several cancers.

miRNA: microRNA is a type of RNA found in cells and in blood. They are smaller than many other types of RNA and can bind to messenger RNAs (mRNAs) to block them from making proteins.

Murine: rodent family, including rats and mice.

Nano-particle: A particle of that is smaller than 100 nanometers (one-billionth of a meter). In medicine, nanoparticles can be used to carry antibodies, drugs, imaging agents, or other substances to certain parts of the body.

Oncogenic: typically an oncogene is a mutant from a normal gene involved in the control of cell growth and division – it will make the cell act more cancerous.

Senescence: as primary cell structures age, cell proliferation slows and terminates.

SV40 virus: Simian virus 40, a polyoma virus of monkeys, which has been a model for the basic studies of viral pathogenesis and for cell transformation and neoplasia.

Ubiquitination: protein inactivation which involves the attachment of ubiquitin to the protein.

Wild-type: Normal, nonmutant form of a macromolecule, cell, or organism.

This glossary was developed using a variety of sources including textbook glossaries, for example Molecular Biology of the Cell, 4th ed. [1] and reputable online dictionaries.


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