The Tumour Suppressor Gene Tp53 Biology Essay

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

The tumour suppressor gene Tp53 is also known as "guardian of genome" is located on chromosome 17 in a cell. The protein encoded by this gene is p53 having a molecular weight of about 53 Kda, contains five domains. They are a transactivation domain, a sequence - specific DNA binding domain, a tetramerization domain, a non-specific DNA binding domain and a proline rich domain (Zhao, Chen & Du 2009). The nuclear phospho protein p53 is a tetramer made up of 393 amino acids.

The activation of this protein regulates many cellular functions. The localisation and stabilization of p53 is dependent on the cellular stress. Generally, p53 is synthesized in cytoplasm, associated with actin filaments and when DNA damage occurs, p53 is imported into nucleus (Aurora, Paraskevi 2003). It has been found that p53 is mutated or inactivated in at least 50% of cancers. The regulatory protein is known to plays an important role in biological responses like apoptosis and cell cycle arrest. Besides that it is also involved in differentiation and development of cell, DNA repair, DNA replication and transcription, Senescence, cell cycle check points. In normal cells during unstressed conditioned the levels of p53 are low and highly unstable that are regulated by Mdm2, as it binds to p53, acts as an ubiquitin ligase for degradation by proteasome. The activation of p53 during stressed conditions is done by phosphorylation at its N-terminal, due to which mdm2 loses its function to bind p53. One of the tumour suppressor proteins ARF, activated by excess activity of E2F and deregulation of β-catenin also accumulates p53. Several protein kinases like MAPK, ATM, ATR, CHK1 and CHK2 are involved in the up regulation of p53 activity. The ability of p53 to bind other transcription factors depends up on some of the modifications at C-terminal domain like acetylation, ribosylation, glycosylation etc. These modifications regulate the transcriptional powers of p53. The signals that cause increase in levels of p53 are radiation like X-rays and UV, chemotherauptic drugs that damage DNA, hypoxia, myc oncogenes etc. It also safe guards us from skin cancer induced by sunlight containing harmful radiations. The mutations in p53 by mutagens like chemicals, radiations and some viruses causes reduced expression of tumour suppression and results in tumour formation.

The p53 family members include p63 and p73 transcription factors. The gene p53 encodes only one protein but the p63 and p73 genes encode two promoters that encode two proteins. The protein p73 is considered as a homologue of p53 as a tumour suppressor, because it can also induce biological process like apoptosis. (Irwin et al. 2000).


The protein p53 plays an important role in obstructing growth and development of cancer. The major advantages of p53 in cancer prevention as a tumour suppressor are cell cycle growth arrest, apoptosis, inhibiting angiogenesis and cell survival. Tumour cells possess some characteristics like evading apoptosis, limitless growth potential and angiogenesis due to mutations of p53.

Cell cycle arrest and DNA repair:

The cell cycle is arrested in response to damage of DNA by transcriptional activation of p53, which prevents the duplication of damaged DNA. The progression of cell cycle is blocked at G1/S and G2/M check points through the expression of p53. Cell cycle is regulated by combinations of various cyclins and cyclin dependent kinases. The check points cdk2/cyclin A, E and cdk1/cyclin B regulates G1S and G2M phase transitions respectively. In the presence of DNA damage, p53 is phosphorylated by several kinases activates protein p21. The protein p21 is an inhibitor of cyclin dependent kinases, is a target of p53.(Harper et al. 1993) The kinase activity of cyclin dependent kinases is inhibited, resulting in arresting of cell cycle. When the cell cycle is arrested, p53 activates DNA repair proteins to fix the damage. The DNA repair genes induced by p53 are p53R2, XPC, XPG, XPE/DDB2, Gadd45 etc repairs the damaged DNA. Thus, it maintains the genomic stability. If the DNA damage is irreparable and cannot be cured, it initiates programmed cell death or apoptosis.

FIGURE 1: The transcription activation of p53 leads to arrest of cell cycle and repair of damaged DNA. The phosphorylation of p53 results in activation of p21 WAF1/CIP1 which blocks cyclin/cdk complex, resulting in G1 arrest. The transcriptional repression of cyclin B by p53 results in G2 arrest. It also activates Gadd45 protein for DNA repair.

Induction of apoptosis:

P53 proceeds to apoptosis during anoxia, signalling imbalances or irreparable DNA damage. Apoptosis is the self-destruction of cells which involves activation of caspases that cleave DNA and engulfment of DNA fragments by phagocytes. Many regulators of apoptosis are found to bind DNA binding domain of p53. It induces apoptosis both in transcription dependent and independent mechanisms (Meulmeester, Jochemsen 2008). In intrinsic pathway it activates genes like bax and PIG, which activates the caspases that cleaves the DNA. It also represses an anti apoptotic gene BCl2, which inhibits apoptosis by inhibiting Bax. The release of cytochrome c from mitochondria is activated by reactive oxygen species. P53 induces several genes called PIG (p53 induced genes), that increase the production of ROS. Thus, cytochrome c is released from mitochondria by the action of bax and PIG, which results in formation of apoptosome and activation of caspase 3. The caspase 3 activates cad endonucleases that cleave the DNA, ending in apoptosis. The extrinsic pathway of apoptosis from p53 involves signals from outside the cell. KLLER/DR5, Fas/APO1 transmit signals to FADD by p53, activating caspases 8, 10 and finally caspase 3. The induction of apoptosis by p53 is also independent on these downstream signalling pathways (Meng, El-Deiry 2001).

FIGURE 2: Induction of apoptosis by p53. P53 triggers bax, PIG, Fas/APO1, KILLER/DR5 intrinsically and extrinsically to activate caspases resulting in apoptosis. It also repress Bcl2, an anti apoptotic gene that inhibits bax. Bax and PIG genes act on mitochondria to release cytochrome c, which forms a complex called apoptosome with APAF 1 and caspase 9. The complex activates CAD through caspase 3 and it cleaves the DNA resulting in death. Fas/APO1 and KILLER/DR5 activates the caspases cascade that results in apoptosis.

Inhibition of Angiogenesis:

The formation of new blood vessels from the existing blood vessels, for supplying of nutrients and oxygen for the growth and development of tumour is inhibited by p53. The mechanisms involved in limiting angiogenesis by p53 are hindering central regulatory units of hypoxia (HIF), repressing production of pro-angiogenic factors and activating anti angiogenic factors (TSP-1). The hypoxia inducible factor (HIf), which promotes the production of new blood vessels through activating genes required for oxygen deprivation responses like VEGF, is inhibited by p53. In normal conditions HIF is not inhibited by p53, but in hypoxic conditions only it is inhibited. Several pro-angiogenic factors which stimulate angiogenesis like VEGF, bFGF, bFGF-BP and COX-2 are transcriptionally repressed by p53. Certain anti angiogenic factors like thrombospondin (TSP-1), brain-specific angiogenic inhibitor 1(BAI1), ephrin receptor A2 (EPHA2) and collagens act against angiogenesis are p53 activated.(Teodoro, Evans & Green 2007)

FIGURE 3: Inhibition of angiogenesis by p53. The regulatory unit of hypoxia, HIF is made up of two subunits HIF-1 α and HIF-1β. The oncogenic activation of p53 results in degradation of HIF-1α by proteosome. Under hypoxia conditions HIF and HIF targeted genes mediate angiogenesis but p53 inhibits angiogenesis by degrading HIF-1α protein.


Cellular senescence is the permanent non growing state of cell i.e. permanent cell cycle arrest, which is caused by damage of DNA or by activated oncogenes.(Chen et al. 2005). One of the types of DNA damage may be due to dysfunction of telomeres. Telomeres are the ends of chromosome that protects the fusion of chromosomal ends and thus, maintains chromosomal stability. The loss of telomeric function causes DNA damage as chromosomes fuse end to end, which in turn activates tumour supressor protein p53. In response to DNA damage, p53 activates through various downstream signalling pathways and arrests the cell cycle to cause senescence. The activated p53 triggers a cyclin dependent kinase inhibitor protein p21, which inhibits CDK activity and thus, arrest cell cycle.

FIGURE 4: pathways of p53 in senescence, G1 arrest and apoptosis with response to telomere dysfunction. The shortening of telomeres causes chromosome end-end fusions leading to breaks in double strands. These breaks activate ATM/ATR kinases which further activate CHK2 and finally phosphorylate p53. The activated p53 induces some genes like p21, Bax, Puma, Noxa resulting in biological processes for tumour suppression.

Regulation of metabolism:

The protein p53 regulates glucose metabolism and functions as a tumour suppressor. Generally, normal cells depend on oxidative phoshorylation for energy but tumour cells depend on glycolysis for energy. This is called Warburg effect. Tumour cells are found to up regulate glycolysis for ATP in order to proliferate continuously. It is known that the cell proliferation is dependent on glucose and the availability of glucose is mediated by AMP-activated protein kinase (AMPK) activation (Bensaad, Vousden 2007). The target molecule of AMPK is p53, which is activated by phosphorylation induces a reversible cell cycle check point, in order of glucose deprivation. In the absence of glucose, p53 activates and arrests cell-cycle.

Oxidative stress:

One of the functions of p53 is to regulate levels of intracellular reactive oxygen species (ROS). The reactive oxygen species in cells regulate the growth and development of tumour. Generally, low levels of ROS are required for proliferation and high levels of ROS results in senescence or apoptosis. In unstressed condition low levels of ROS are maintained by anti oxidant proteins like sestrins. During stress conditions p53 activates genes which encode pro-oxidant enzymes that increase ROS levels. They include PIG-3, proline oxidase and mitochondrial respiration activating genes (Bensaad, Vousden 2007). It also inhibits anti oxidant genes. As a result of increase in levels of ROS, cell death occurs by apoptosis.

Induction of miRNA:

The transcriptional activator p53 is found to induce small non coding RNAs of 20-25 nucleotides called microRNAs (miRNAs). These miRNAs are post-transcriptional regulators that bind to protein-coding messenger RNAs, blocking translation and therefore, reducing the protein expression. The protein p53 enhances transcription of miR-34 gene family, resulting in production of miRNAs, which promote senescence or apoptosis (He et al. 2007). The regulation of anti-proliferative miRNAs miR-16-1, miR-143 against DNA damage is done by p53. The tumour suppressor is found to associate with drosha complex that converts primary miRNa into precursor miRNA (Suzuki et al. 2009). The miRNAs 15a/16 are induced by p53 are found to repress anti-apoptotic genes BCl-2 and Ras oncogenes (Tarasov et al. 2007).


In addition to the advantages of p53 in cancer prevention, some disadvantages are also identified. A single mutation of p53 gene leads to destruction of many signalling pathways, resulting in tumour progression. The mutation of this tumour suppressor gene causes enhanced genomic instability through proliferation and evading cell cycle check points. Thus, loss of function of p53 gives additional advantage of cancer cells to survive. Other effects include inducing angiogenesis, susceptibility to many cancers and activation of oncogenes.

Cellular ageing:

The major side effect of p53 is premature cellular ageing. The disorder of cell ageing caused by p53 is called as Werner syndrome, which is human autosomal recessive disease (Shen, Loeb 2001). Normally p53 is activated in response to DNA damage and if the damage is irreparable it leads to senescence or apoptosis. The WRN protein which is responsible for preventing ageing is associated with p53. The c-terminal domains of both proteins interact with each other. In response to DNA damage, over expression of WRN proteins cause the levels of p53 to accumulate and therefore inducing protein p21 (Blander et al. 1999). The expressed p21 protein inhibits cyclin dependent kinases of cells cycle and thus, blocking the cell cycle and resulting in senescence. Hence, a relationship exists between WRN proteins and p53 for maintaining genome integrity and avoiding premature senescence.

Pro-survival property of cancer cells:

Cancer cells gained the survival advantage of p53 function. The survival function of p53 by DNA repair mechanism is also dominant over apoptosis. In Glioblastoma multiforme (GBM), a form of brain cancer in humans, the glioma cells with p53 show destruction of apoptosis and strength to DNA repair and cell cycle control (Kim, Giese & Deppert 2009). This is due to block of pro apoptotic genes and over expression of anti apoptotic genes by p53. The protein maintains a balance between death causing apoptosis and pro-survival. Thus, cancer cells acquire survival potential by p53.

Li-Fraumeni syndrome:

The germ line mutations of TP53 gene cause Li-fraumeni syndrome, an autosomal dominant familial cancer syndrome (Dockhorn-Dworniczak et al. 1996). This syndrome is characterised by breast cancers, soft tissues and other risks of malignant neoplasms. The mutant p53 alleles associated with this disorder showed point mutations in reading frame. The DNA binding domain of p53 is altered and as a result of this, the protein cannot regulate cell cycle and cannot induce apoptosis. This causes vulnerability to many tumours.

Most of the cancers arise because of mutations in p53 gene. The loss of p53 function through mutations is more advantageous to cancer cells. The transcriptional activity of p53 is lost due to inactivation of DNA binding domain, which affects many downstream signalling pathways for biological processes. The mutations of p53 promote cell cycle with the damaged DNA, due to which mutations accumulate leading to formation of tumour. Hence, genomic stability of cell is lost through aneuploidy, which favours cancer formation. These mutations results in activation of oncogenes and inactivation of tumour suppressor genes. The activated oncogenes include Myc, Ras, Akt, Bcr-abl, etc functions in growth of tumour. The metabolism of cells is also affected by mutation of p53, as it changes the expression of metabolic enzymes and inhibits oxidative phosphorylation and stimulates glycolysis (Bensaad, Vousden 2007). Cancer cells acquire the ability to survive and proliferate in conditions of anoxia, due to the loss of response to apoptosis caused by the improper functioning of p53. The angiogenesis of tumour cells for supply of oxygen and nutrients also sustains as inactivated p53 cannot induce expression of TSP-1 gene that is important for inhibition of angiogenesis. The other consequences of p53 loss are genetic instability due to accumulation of reactive oxygen species (ROS), which induces growth and development of tumour.

FIGURE 5: Mutations in p53 leads to a formation of cancerous cell. The mutated p53 cells lose their ability to arrest cell cycle and repair the damaged DNA, in response to DNA damage. Finally, the mutations accumulate giving rise to tumours.


The tumour suppressor p53 plays a vital role in most of signalling pathways essential for cancer prevention. The regulation pathways of p53 are very complex. The levels of nuclear phospho protein p53 are regulated by Mdm and ARF. The signals received by p53 from various kinds of stresses induce cell cycle growth arrest, senescence, apoptosis, angiogenesis etc. P53 acts as a key controller for all the physiological process.

In response to DNA damage by genotoxic stress or oncogenic stress, p53 activates various kinases transcriptionally, resulting in cell cycle arrest or apoptosis or senescence. It induces DNA repair genes for fixing DNA damage, if the damage is repairable. In the presence of irreparable damage, p53 promotes cell death by apoptosis or permanent cell cycle arrest (senescence). Therefore, it is called as guardian of genome as it maintains genomic stability. During the conditions of anoxia (extreme low levels of oxygen), p53 phosphorylates and triggers apoptosis in both transcription depend and transcription independent pathways. The hypoxia inducible factor in blocked during low levels of oxygen (Hypoxia) and thus, inhibiting angiogenesis. It also represses several pro-angiogenic factors and activates anti-angiogenic factors that are involved in angiogenesis. The transcriptional activator functions as a tumour suppressor in regulating glucose metabolism and intracellular reactive oxygen species. Another function of p53 is to inhibit protein expression via miRNAs. It induces transcription of miR-34, repression of anti apoptotic proteins and regulation of anti proliferative proteins. From the above context, p53 is used as a main target molecule for cancer therapy.

Some of the disadvantages of p53 in cancer prevention are premature cell ageing and survival advantage of cancer cells. The presence of p53 in cancer cells shows a survival advantage by impairing apoptosis. Mutations in p53 are a gain of function that causes loss of tumour suppressor activity and advantage to progression of tumour. The mutated p53 induces expression of proteins that are involved in cell proliferation, survival and angiogenesis. Point mutations in p53 are responsible for many disorders like Li-fraumeni syndrome, which causes increased susceptibility to many tumours. Tumour cells with mutated p53 gain the ability to grow and proliferate due to the absence of cell cycle check points and apoptosis.

Several chemotherapeutic agents are developed using p53 as it induces apoptosis and resulting death of tumour cell. Because of the involvement of p53 in regulation and prevention of cancer, a number of therapeutic strategies have been discovered to cure cancer using this gene.