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    The p53 Gene

    Date: August 3, 2024

    by P. C. Venkat

    Meet the Tumor Suppressor Protein

    One of the important mechanisms in a cell is the work of an amazing protein that does something unexpected: the p53 Tumor Suppressor protein. As its name implies, it suppresses the effects of genetic aberrations that would otherwise give rise to tumors. Its encoding is the function of a gene called the TP53 gene - also sometimes referred to as the p53 gene. Often this gene is also identified by its chromosome location: '17p'. Don't be confused by the names — as far as we are concerned, this is one important gene and the protein it encodes does a critical job.

    Most proteins are complex; this one is just a little more so. Spatial geometry is important in the function of any protein, its three-dimensional architecture determining how it interfaces with other complex molecules to perform its vital task. The p53 protein is unique in that it is also flexible; its intricate three-dimensional architecture is given another dimension of versatility by this flexibility. It actually consists of five distinct segments linked together by long, bendable strands that give it this flexibility. The multi-part nature of this molecule gives it a unique ability to wrap around segments of DNA that may have been damaged, thereby altering the manner in which the genetic code in the damaged segment is expressed within the cell.

    Here is what the protein looks like. The appearance of the molecule does give a clue to its unique behavior.

    p53 protein

    The p53 protein in its unbound state

    Image courtesy of RCSB,
    Research Collaboratory for Structural Bioinformatics

    The Tumor Suppressor swings into action when a cell experiences an event or process that causes damage to its DNA.

    The damage could be caused by radiation, a mutagenic chemical, a virus or some other error introduced in replication. When a sensitive part of the DNA is damaged by such an event, the internal workings of the cell are disrupted in unexpected ways and the cell malfunctions. Most malfunctioning cells simply cannot live a normal life and die of their own accord or in response to intercellular signals that precipitate programmed cell death (apoptosis). However, some specific types of damage to the DNA cause the cell to become resistant to programmed cell death and in fact confer on it the equivalent of cellular immortality. This is often coupled with signals to grow and divide, so that one affected cell can pass on this damaged DNA to its daughter cells and soon become a colony of clones, characterized by uncontrolled tissue growth – a tumor. Fortunately, most animals, from worms to humans, have evolved p53 as a safeguard at the cellular level to combat this very possibility.

    Normally, the p53 protein is found at low levels within the cell. However, when DNA damage occurs, the level of p53 rises and the Tumor Suppressor starts its repertoire of protective measures. It binds to many regulatory sites in the DNA helix and begins production of proteins that halt cell division. If the damage cannot be repaired, p53 begins the process of programmed cell death so that the damaged DNA cannot be passed on to other tissue cells. Ergo, the tumor is stopped in its tracks! The presence of fully functional p53 Tumor Suppressor protein within the cell has reversed or corrected the effect of a damaging mutation.

    p53 protein

    The p53 protein bound to a DNA segment

    Image courtesy of RCSB,
    Research Collaboratory for Structural Bioinformatics

    How does p53 do its magic? In normal cells, p53 is expressed at low levels with a short half-life. It is exported out of the cell's nucleus as soon as it is produced and resides in the cytoplasm, where it degrades in a short time. In fact in normal cells, the presence of p53 within the nucleus would inhibit normal cell growth. However, when damage to DNA occurs within the cell, an intra-cellular signal activates cellular p53 protein as well as the gene that encodes this protein, the p53 gene. The activation of this gene increases the production of p53 protein. The p53 molecule builds up in the nucleus and homes in on the damaged segment of the DNA. The four arms wrap around and clamp on to the helical segment in pairs, one pair at a specific binding site and the other pair at another specific binding site several base pairs removed from the first. The p53 domains in contact with the DNA are able to regulate the transcription of the DNA in these regions and can activate neighboring proteins involved in reading the DNA. The effect is to correct the misreading of the genetic code from the damaged segment of DNA. Other p53 molecules bind to additional damaged sites along the DNA helix, regulating transcription at these sites. Meantime, the level of p53 in the cell accumulates and arrests the cell in the “G1” phase of the cell cycle, wherein it can synthesize proteins through gene expression but cannot synthesize DNA and start the replication process. The cell cannot divide. If the damage is minor or if the cell’s repair mechanisms are up the to job of correcting the genetic flaw, the cell goes back to its business and the damage control systems stand down - p53 goes back to watchful waiting. If the damage is sufficiently severe, the level of p53 in the cell accumulates beyond a critical level, triggering apoptosis and the cell dies without replicating itself.

    This is not to say that all genetic damage can be corrected or reversed in this fashion. There are some critical types of DNA damage that are resistant to repair and confer resistance to programmed cell death even in the presence of p53. In these cases, a tumor may originate anyway. But tumor incidence would be a lot more frequent in the absence of the Tumor Suppressor protein.

    There is of course the possibility that the gene encoding for the p53 protein (TP53) can itself become damaged or deleted. Many of the more serious cancer phenotypes are associated with damage to or deletion of the DNA segment encoding for this molecule, the TP53 gene. In fact, damage to or deletion of the p53 gene is associated with about 50% of all human cancers. This gene is sometimes identified by its "gene map locus ID", 17p13.1, identifying the gene's location on chromosome 17 in the human genome.

    Most cases of damage to the TP53 gene involve the swapping of an incorrect amino acid at a particular location on the protein that it encodes. This causes blockage of the normal function of the p53 protein rendering it unable to stop multiplication of the damaged cell. This is akin to your anti-virus program failing. The real damage occurs if the cell also has another mutation that causes uncontrolled growth. A tumor then develops. You know that if you surf around enough on the Internet without the protection of an anti-virus program, you are going to be hit with a computer virus sooner or later. Drawing an analogy with the virus-ridden cyber-world, you may conclude that a cell (or a colony of cells - a body of tissue) living in a normal (mutagenic) environment without the protection of fully functional p53, is going to experience another mutation sooner or later that will give rise to a tumor. The normal alert, repair, quarantine and delete mechanisms are not at work in this case. This is why a p53 mutation or deletion is the single most common genetic cause of tumors and why tumors lacking p53 modulation are comparatively more malignant than those where p53 is still functional. Further, p53 deletion can lead to the accumulation of additional mutations in the resulting body of tumor tissue - the tumor can "transform". This, as we all know, is not good news.

    How often have you read, "...patients with TP53 deletion had significantly shorter median overall survival compared with those without a deletion"? The technical literature agrees that TP53 deletion may be seen as a prognostic indicator of poor outcome. Now you know why.

    There is also evidence that the aberrant p53 protein encoded by certain mutations in the TP53 gene can not only be ineffective at its regular job but in fact have a role in promoting tumors: in this instance, a mutant TP53 gene acts as an oncogene. This, by all logic, is really bad news, worse than even the deletion of the TP53 gene.

    Let us put all this in terms that can be useful to a CLL patient: knowing his phenotype can be important in understanding and choosing among the therapy options open to him. The article titled Genetic Abnormalities in Blood Cancers in the Disease Characteristics section identifies a p53 deletion as being present in 7% of the CLL cases reviewed in the German study quoted. This defect also corresponds to the shortest median survival time of all the mutations identified in the study, 36 months. Knowing this, a patient who knows he has a p53 deletion in his phenotype will probably want to take aggressive action, sooner rather than later. There is also evidence that p53 deletions can be acquired as a result of chemotherapy. Many chemotherapeutic agents like fludarabine or cyclophosphamide function by damaging the DNA of cancer cells, thereby inducing apoptosis. However, if p53 is not present to arrest cell growth, shut down replication and induce apoptosis, the cell with the mangled DNA can continue to grow and multiply. This is one possible genetic mechanism to explain the real-world fact that the disease can transform to a more malignant variety after chemotherapy treatment, a risk well known to patients and oncologists. The good news in all this, of course, is that p53 deletion appears only in a relatively small minority of CLL cases. In the majority of cases, the fully functional p53 protein is present in the neoplastic cells. This doubtless contributes to the relative stability and indolence of the disease as a whole.

    You may now want to read the abstract below describing a "Stable and Indolent Phenotype". The abstract identifies the presence of an unmutated p53 gene as a key feature of "highly stable and indolent disease". Another article that should interest you is titled, "Cytogenetics of ATM and TP53". It examines cellular mechanisms involving these two genetic aberrations that are critical in the progression and aggressiveness of CLL. If these articles have grabbed your attention, you may want to go on and read about the role of Epigenetics in the development and possible treatment of cancer.


    1) Tumor Protein p53. OMIM (Online Mendelian Inheritance in Man) Database at NCBI.

    2) The p53 Website. Institut Curie / Université Pierre & Marie Curie, Paris.

    3) How Tumor Suppressor Gene p53 Keeps Cancer at Bay. Harald Franzen, Scientific American, June 8, 2024.


    Blood. 2024 Apr 3 [Epub ahead of print]. Related Articles, Links

    Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features.

    Guarini A, Gaidano G, Mauro FR, Capello D, Mancini F, De Propris MS, Mancini M, Orsini E, Gentile M, Breccia M, Cuneo A, Castoldi G, Foa R.

    Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita 'La Sapienza', Rome, Italy.

    Different biologic features have been associated with a more or less aggressive clinical course in chronic lymphocytic leukemia (CLL). In the present study, 20 patients with highly stable CLL observed at a single institution over a period of 10-23 years and who never required treatment have been extensively characterized. The aim was to identify a distinct and reproducible biologic profile associated with disease stability that may be utilized to recognize at presentation CLL patients who are likely to have a very benign clinical course and for whom treatment is not indicated. The results obtained indicate that numerous parameters are closely associated with disease stability: a typical CLL morphology and immunophenotype, the lack of expression of the CD38 antigen, the mutated IgVH pattern, the absence of p53 mutations, a CD4/CD8 ratio >1, the lack of 17p and 11q deletions, as well as of complex karyotypic aberrations, and the occurrence of the 13q14 deletion. No case displayed the VH3-21 gene that has been linked in mutated CLL with a poor outcome. In addition, the VH1-69 gene associated with unmutated CLL cases was never detected. These biologic features were coupled with an indolent clinical course characterized by an unmodified clinical stage from diagnosis to the time of this study, lack of autoimmune phenomena and of major infections requiring parental antibiotics. At a time when aggressive therapeutic strategies are always more frequently being utilized in the management of CLL, the distinctive features of patients with long- lived stable disease should be prospectively identified at presentation.

    PMID: 12676780


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