P53 (TP53) Tumor Protein: Function, Mutation

Tumor protein 53, more commonly known as p53, is a protein product of a stretch of deoxyribonucleic acid (DNA) on chromosome 17 in humans and elsewhere in other eukaryotic organisms.

It is a transcription factor, meaning that it binds to a segment of DNA that is undergoing transcription into messenger ribonucleic acid (mRNA).

Notably, the p53 protein is one of the most important of the _tumor suppressor genes_. If that label sounds impressive and hopeful, well, it's both. In fact, in about half of cases of human cancer, p53 is either improperly regulated or is in a mutated form.

A cell without enough of, or the right kind of, p53 is akin to a basketball or football team competing without its top defensive player; only after the unheralded but critical element is out of the mix does the extent of damage that had previously been prevented or mitigated by that element become fully evident.

After a eukaryotic cell divides into two identical daughter cells, each genetically identical to the mother, it starts its cell cycle in interphase. Interphase in turn actually includes three stages: G1 (first gap phase), S (synthesis phase) and G2 (second gap phase).

In G1, the cell replicates all of its components except for its genetic material (the chromosomes containing a complete copy of the organism's DNA). In S phase, the cell replicates its chromosomes. In G2, the cell in effect checks its own work for replication errors.

Then, the cell enters mitosis (M phase).

_Mitosis is much shorter than interphase, and it includes the stages of prophase, prometaphase, metaphase, anaphase and telophase_. (Some educational sources, especially older ones, omit prometaphase.)

During mitosis, the chromosomes condense and align along the central axis of the cell, and the nucleus divides into two daughter nuclei.

Then the cell as a whole divides (cytokinesis) into two new daughter cells to complete the cycle.

The p53 gene codes for a product that comes in "wild type" (which, despite the name, simply means "normal") and mutant forms.

The wild-type protein is the product that is active in tumor suppression. The mutant type, however, not only is dominant over the wild type, meaning that it negates normal p53 function, but it may even be tumor-promoting, or _oncogenic_, on its own.

Thus, inheriting one mutant copy of the p53 mutant gene and one of the p53 tumor suppressor gene is more adverse than not having p53 in your genome at all.

It gets worse. Tumors with mutant p53 copies show resistance to conventional chemotherapy treatment, so not only does inheriting the p53 gene mutation predispose people to cancer, it makes those tumors and cancer cells unusually difficult to treat.

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How does p53 work its tumor-suppression magic? Before diving into that, it's helpful to learn what this transcription factor does more generally within cells, in addition to its key role in helping to prevent an untold amount of malignant diseases in human populations.

Under normal cell conditions, inside the cell nucleus, p53 protein binds to DNA, which triggers another gene to produce a protein called p21CIP. This protein that interacts with another protein, cdk2, which normally stimulates cell division. When p21CIP and cdk2 form a complex, the cell becomes frozen at whatever phase or state of division it is in.

This, as you will see in detail shortly, is especially pertinent in the transition from the G1 phase to the S phase of the cell cycle.

Mutant p53, in contrast, cannot effectively bind to DNA, and as a result, p21CIP cannot serve in its usual capacity to signal cell division to cease. As a consequence, cells divide without restraint, and tumors form.

The defective form of p53 is implicated in a variety of malignancies, including breast cancer, colon cancer, skin cancers and other very common carcinomas and tumors.

The role of p53 in cancer is its most clinically relevant function for obvious reasons. However, the protein also acts to ensure smooth functioning in the vast number of cell divisions that occur in the human body every day, and that are unfolding in you at this moment.

While the boundaries between stages of the cell cycle may seem arbitrary and perhaps suggest fluidity, cells demonstrate distinct checkpoints in the cycle – points at which any issues with the cell can be addressed so that errors are not passed to daughter cells down the line.

That is, a cell would sooner "choose" to arrest its own growth and division than proceed despite pathological damage to its contents.

For example, the G1/S transition, right before DNA replication occurs, is considered a "point of no return" for cells to divide. p53 has the ability to halt cell division at this stage if necessary. When p53 is activated at this step, it leads to the transcription of p21CIP, as described above.

When p21CIP interacts with cdk2, the resulting complex can prevent cells from passing the point of no return.

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The reason p53 might "want" to put a stop to cell division has to do with problems in the cell's DNA. Cells, left to their own, will not start dividing uncontrollably unless there is something amiss in the nucleus, where the genetic material lies.

Preventing genetic mutations is a key part of controlling the cell cycle. Mutations that are passed on to future generations of cells can drive abnormal cell growth, such as cancer.

DNA damage is another reliable trigger of p53 activation. For example, if DNA damage is detected at the G1/S transition point, p53 will halt cell division via the multi-protein mechanism outlines above. But apart from participating in customary cell-cycle checkpoints, p53 can be summoned into action on demand, when the cell senses that it is in the presence of threats to DNA integrity.

p53, for example, becomes activated when it detects known mutagens (physical or chemical insults that can cause DNA mutations). One of these is ultraviolet (UV) light from the sun and artificial sources of sunlight such as tanning beds.

Certain kinds of UV radiation have been solidly implicated in cancers of the skin, and thus when p53 perceives that the cell is experiencing conditions that could lead to unchecked cell division, it moves to shut down the cell-division show.

Most cells do not go on dividing indefinitely throughout an organism's life.

Just as a person tends to accumulate visible signs of "wear and tear" with aging, from wrinkles and "liver spots" to scars from surgeries and injuries incurred over a period of decades, cells, too, can amass damage. In the case of cells, this takes the form of accumulated DNA mutations.

Doctors have long known that the incidence of cancer tends to rise with advancing age; given what scientists know about the nature of old DNA and cell division, this makes perfect sense.

This condition of having piled up age-related cellular damage is called senescence, and it builds up in all older cells over time. Not only is senescence in itself not problematic, but it normally provokes a planned "retirement" on the part of affected cells from further cell division.

The hiatus from cell division protects the organism because the cell does not "want" to risk starting to divide and then be unable to stop because of the damage inflicted by DNA mutations.

In a way, this is like a person who knows he is sick with a communicable disease avoiding crowds so as to not transmit the relevant bacteria or virus to others.

Senescence is governed by telomeres, which are segments of DNA that become shorter with each successive cell division. Once these shrink to a certain length, the cell interprets this as a signal to proceed into senescence. The p53 pathway is the intracellular mediator that reacts to short telomeres. Senescence thus guards against the formation of tumors.

"Systematic cell death" and "cell suicide" certainly do not sound like terms that imply circumstances beneficial to the cells and organisms affected.

However, programmed cell death, a process called apoptosis, is actually necessary for the health of the organism because it disposes of cells that are especially likely to form tumors based on telltale characteristics of these cells.

Apoptosis (from the Greek for "falling away") occurs in all eukaryotic cells under the guidance of certain genes. It results in the death of cells the organisms perceives as damaged and therefore a potential hazard. p53 helps regulate these genes by increasing their output in target cells to prime them for apoptosis.

Apoptosis is a normal part of growth and development even when cancer and dysfunction is not at issue. While most cells may "prefer" senescence to apoptosis, both processes are vital to preserving the well-being of cells.

Based on the foregoing information and emphasis, it is above, it is clear that the primary job of p53 is to prevent cancer and the growth of tumors. Sometimes, factors that are not directly carcinogenic in the sense of directly damaging DNA can still increase the risk of malignant disease indirectly.

For example, the human papillomavirus (HPV) can increase the risk of cervical cancer in women by interfering with the activity of p53. This and similar findings about p53 mutations underscore the fact that DNA mutations that can lead to cancer are extremely common, and that were it not for the work of p53 and other tumor suppressors, cancer would be extraordinarily common.

In brief, a very high number of dividing cells are plagued with dangerous DNA errors, but the vast majority of these are rendered ineffectual by apoptosis, senescence and other safeguards against uncontrolled cell division.

p53 is perhaps the most important and well-studied cellular pathway for combating the lethal scourge of cancer and other diseases contingent on faulty DNA or other damaged cell components. But it is not the only one. Another such pathway is the Rb (retinoblastoma) pathway.

Both p53 and Rb are kicked into gear by oncogenic signals, or signs interpreted by the cell as predisposing the cell to cancer. These signals, depending on their precise nature, can inspire the up-regulation of p53, Rb or both. The result in both cases, albeit through different downstream signals, is the cell cycle arrest and an attempt to DNA repair any damaged DNA.

When this is not possible, the cell is shunted toward either senescence or apoptosis. Cells that evade this system often go on to form tumors.

You can think of the work of p53 and other tumor suppressor genes as taking a human suspect into custody. After a "trial," the affected cell is "sentenced" to apoptosis or senescence if it cannot be "rehabilitated" while in custody.

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