Chapter 13 Chapter 13 Assisted Suicide: Apoptosis and the Death Program

The generation clock is a way for the body to control the number of cells.But the body has at least another strategy for restricting cell proliferation that works in the same way.Human tissue can induce redundant or defective cells to commit suicide.Cancer cells must have mastered the art of dodging the death machine.This is another way for the human body to thwart cells on the road to malignant cancer.Embryologists have long discovered that organisms can selectively destroy certain cells within tissues.Perhaps the most impressive example is the development of the human hand.Initially, large sheets of connective tissue held the fingers together.Later, most of the cells in the connective tissue died, leaving only some residual tissue at the base of the finger.But during embryonic development, there are many other, less dramatic places where the mass destruction of cells also occurs.In the brain, for example, the large embryonic nerve cells that failed to form proper connective tissue fell victim to it.

Eliminate useless cells, this practice has been around since ancient times.This killing phenomenon can be clearly seen in a primitive animal, which in many ways is very similar to the distant ancestor of human beings 600 million years ago.The worm is a microscopic worm whose egg divides repeatedly after fertilization to produce 1090 cells, of which 131 cells die at a specific point in embryonic development. Until recently, most biologists assumed that these cells gradually collapsed, dying from natural attrition, starvation, or damage to their vital organs.This slow death is similar to some necrosis caused by poisoning.In necrosis, the cell swells up, its internal components fall apart, and finally the cell bursts and dies.

We now know that many cells, ingeniously, took another path of no return.They actually adopt a fast and rigid pattern.Some kind of internal death program determines the cell's death. Andrew Wyllie in 1972. One of the discoverers of programmed cell death, called "apoptosis".The word is of Greek origin and means to shed a leaf.Once the death process is triggered, the cell dies, disintegrates, and the remains disappear, all of which take place in less than an hour. Apoptotic death appears to be programmed into the control system of every human cell.This self-destruct mechanism is very similar to the explosive devices that rocket manufacturers install in satellite launchers.If the rocket deviates from orbit, ground controllers will detonate the self-destruct device.Likewise, a derailed or useless cell is targeted for destruction, a decision made either by surrounding tissue or by the cell's own internal control system.

The process of apoptosis is depressing.First, the cells shrink.Then, multiple outer membranes protrude.Before long, the DNA fragments of the cell's chromosomes fall apart.Finally, the cell bursts and its fragments are quickly engulfed by its neighbors.There is no trace behind the cells, just like a mirror and a pillow. Intuition tells us that the period of embryonic development should be a period of vigorous expansion.At the moment, the carefully planned embryo seems to produce only those cells necessary to build tissue, neither more nor less.However, apoptosis in large numbers during embryonic development runs counter to our intuition.In fact, the development of embryos is surprisingly inefficient and wasteful.In the developing embryo, there are many places where cell division produces far more cells than is necessary to form the final organ or tissue.Some of these cells form evolutionary remnants of tissues that are of no use to modern organisms.Other cells are the product of failed efforts to build proper tissue during embryonic development.Apoptosis is like a sculptor's chisel, mercilessly removing useless cells.

Recent studies have shown that not only during embryonic development, but organisms employ apoptosis throughout their lives.In the immune system, cells that cannot make appropriate antibodies are largely discarded.Many formed tissues use apoptosis to continuously screen and maintain their internal structure. Mammalian cells also employ an apoptotic death program in other situations.Cells infected with various viruses strive to activate the apoptotic program.Their motivation is clear: to end the virus' growth cycle by rapidly sacrificing itself and depriving it of a suitable host to reproduce.This noble act of altruism spares peripheral cells from the danger of continued infection.To counteract this defense program, many viruses have developed countermeasures that rapidly shut down the host cell's apoptotic response.

Apoptosis is the only option for cells in the body that are clearly defective, especially if their DNA has been severely and irreparably damaged.In some unknown way, cells are able to sense when their genome is badly damaged.Instead of trying to repair the wound, the cell commits suicide as prescribed. However, many cells that were only slightly injured and still alive were sent on the path to apoptosis.At first glance, this suicide seems wasteful.Tissues are constantly generating new cells, hosting those that are culled for only slightly defective ones, squandering useful resources.Still, this drain on resources pales in comparison to the eventual risks of keeping a damaged, perhaps mutated cell alive.This shows that an important function of apoptosis is to quickly eliminate deviant cells in tissues throughout the body to prevent them from causing trouble to the party.

The slightest loss of control in the growth control system inside the cell triggers the death process.This loss of control can occur inside cancer cells and is associated with metabolic imbalances and improper growth signaling.For example, injecting a myC oncogene into a normal cell causes a signaling imbalance that causes many cells to initiate an apoptotic death program.That is to say, many cells that have acquired the Sichuan yC oncogene through some accidental mutation will die of apoptosis rapidly.Perhaps a small part of them escaped the inevitable death by one way or another.In fact, cells are programmed to commit suicide when an oncogene is activated within them.Organisms have mine wires embedded in all their cells.These alarm devices build roadblocks for the formation of tissue tumors by causing early cancer cells to kill themselves quickly.

We believe that cells on the road to cancer must have carefully studied the minefield of apoptosis.After acquiring a growth-promoting oncogene, cells must try to avoid apoptosis.This dodge is sometimes accomplished through a second mutation.For example, an activated myC oncogene often triggers apoptosis, but under certain conditions, subsequent activation of the ras oncogene allows cells to avoid apoptosis. The role of mutations in evading apoptotic death is best illustrated by the immune system.As mentioned earlier, if immune cells cannot produce appropriate antibodies, they will be eliminated by apoptosis.A certain type of lymphocyte is the protagonist in the development of the immune system, of which more than 95% of the cells are discarded in this way.We now see that the cells eliminated by tissues include not only obviously defective and life-threatening cells, but also those that are merely non-productive.

Lymphocytes' fight against this death program also leads to cancer. The BC2 oncogene specifically prevents the triggering of the death program, and by activating the gene, lymphocytes can make a triumphant escape.Lymphocyte populations with an active BC2 oncogene will begin to expand massively, escaping the almost inevitable fate of apoptosis.These cells are not malignant, they just accumulate in huge numbers.After a few years, however, some of these incremental cells might undergo other mutations, including the activation of the peri Uc oncogene, and they would then become truly malignant progeny, leading to lymphoma.More and more evidence shows that there are other types of cancer cells that either mutate or overexpress the BC2 oncogene to activate BC2 to ensure their long-term survival.

Among all kinds of cancers, judging whether they belong to precancerous cells purely from the number will give the tumor a chance to gain full-fledged wings.To form lethal tumors, cells must not only increase their ability to reproduce but also find ways to evade death.Some populations of precancerous cells may succeed in increasing their reproductive rate by acquiring an active oncogene, but they may not escape the threats of apoptosis and aging; Even faster cell death is counteracted.The net gain in cell populations may be constant size or even shrinkage.Only by addressing cell death can cell populations begin to expand rapidly, leading to Malthusian growth". Guardian of the genome, master of the death program: p53

There are many central controllers that influence a cell's decision to make apoptosis or not, the best known of which is the p53 tumor suppressor gene.It functions through its own proteins, becoming the referee of life and death and the vigilant guard in charge of the health and well-being of cells.It sounds the death knell when the cellular machinery is damaged or when the cell starts to misbehave.The role of p53 is most prominent in the cell's response to damage to its own DNA. Human cell genomes are always in a precarious state amid the erratic replication errors of DNA polymerases.Cells respond to genetic damage in one of two ways: either they attempt to compensate for the defect using the repair mechanisms we have described previously, or they resign themselves to apoptosis.If the damage caused by the mutation is small, the cell will make an effort to repair it; if it is severely damaged, the repair mechanism is not strong enough, and the cell has no choice but to die. Cells generally rely on the p53 protein to help sense DNA damage.Like other tumor suppressor proteins, the p53 protein prevents cell proliferation, giving repair mechanisms time to search for and repair damaged base sequences.Once the damage is removed, p53 kicks in, allowing the cells to continue growing. The logic behind this response is simple.Pausing prevents cells from entering the growth phase that requires DNA replication.Only when the DNA damage has been successfully repaired does the p53 protein issue a license to enter the DNA replication phase, ensuring that the replicase -- DNA polymerase -- does not inadvertently replicate the damaged DNA, allowing mutations to be passed on from generation to generation , producing progeny cells with the same defect. If the DNA is extensively damaged, there will be a very different response.As before, the p53 protein in the cells reached a very high concentration.Cells are again forced to stop growing.But this time, the cell's damage-assessment mechanisms will weigh the extent of the genetic damage to decide whether to activate another response: the initiation of the apoptotic program.The results were swift and unambiguous: The cell died within about an hour, along with its newly battered genes.Yes, the sacrifice of apoptosis is a significant waste of biochemical resources, but in the long run, this option is very cost-effective compared to the emergence of a certain mutant, highly cancerous cell in the tissue. The benefits of inactivating the p53 gene through mutations in early cancer cells are clear.Once a cell knocks out the p53 gene, it severely weakens its own damage response pathways.One consequence is that cells can continue to reproduce even if the genomes of the cells and their descendants are severely damaged.In the absence of a functioning H53, these cells would replicate their already damaged DNA by leaps and bounds, incorporating unrepaired dysfunction into newly produced genome replicating enzymes.Thus, the mutant genome can be extended endlessly. Normally, activating proto-oncogenes and inactivating tumor suppressor genes is a slow mutation process, but if there is no dedicated p53, this process will be greatly accelerated.Because these mutational events limit the rate of tumor expansion, Hu53's silence will greatly accelerate the evolution of tumor cell populations, allowing mature tumors to appear earlier.Altogether, the loss of p53 destroyed a stable genome, as did a major defect in the DNA repair machinery. Normal cells in a dish have a slight, almost imperceptible tendency to overaccumulate copies of genes.But in the absence of functioning p53, this propensity to overaccumulate gene copies is 1,000-fold greater.As mentioned earlier, this gene "amplification" will lead to increasing copies of growth-promoting oncogenes such as mpc, erb B and erb BZ/neu.Many types of cancer, such as brain, stomach, breast, and ovarian cancers, as well as childhood retinal gliomas, frequently show amplification of these genes during their development. Almost all tumor cells have mastered the ability of immortality, and the inactivation of P53 has helped the process of tumor cell immortality.The undead barrier is the shrinking and disintegration of telomeres.Once the telomeres are depleted to a certain extent, the first alarm will be sounded inside the cell, the growth will stop, and it will enter the state of twilight.Cells seem to sense telomere shortening in the same way they sense DNA damage.In response to this urgent genetic event, cells mobilize p53, usually by shutting down the cell's growth.These cells will remain in a quiescent state for a long time. Cells without p53, blind to telomere depletion, continued to grow.They charge forward and continue to multiply for another 10 or 20 generations, leaving aging far behind.At this time, as the telomere continues to shorten, to a certain extent, a second alarm is sounded in the cell.At this time, the cells will die in large numbers, and only those few mutant cells that have been revived with remgranase can escape this catastrophe, repair their telomeres, and gain immortality.Although inactivation of p53 does not create immortal cells, it does give tumor cells a chance to compete for the golden belt—immortality by reviving telomerase. Recently, another side of p53 inactivation has been revealed.Cancer cells in a tumor mass are starved of oxygen due to lack of blood supply, and because of hypoxia -- oxygen starvation -- they stop growing.If the hypoxic state of normal cells lasts too long, the cells will undergo apoptosis. p53 appears to be a mediator of the response.The p53 gene in many tumor cells will be mutated and inactivated, and these cells have extraordinary tolerance, and can persist until the moment when sufficient blood supply is successfully established, and then resume unimpeded rapid proliferation. The state of p53 protein in cells also has a direct impact on cancer treatment.Almost all treatments for cancer—chemotherapy and radiation—operate by damaging tumor cells.Chemotherapy can directly act on DNA bases, alter DNA structure; or affect DNA replicating enzymes. X-rays can also cause irreparable damage to the DNA double helix. For 30 years, it was assumed that these anticancer therapies could kill cancer cells by damaging DNA extensively.This disruption, of course, overwhelms the cancer cell's repair mechanisms.As the DNA of the cancer cell's chromosomes is torn to shreds, the cancer cell stops growing and dies. We now know that anticancer therapies often go the other way.Chemotherapy and X-rays, given in doses sufficient to kill cancer cells, do not actually cause extensive damage to the cancer cell's genome.Instead, the treatments caused just enough damage to activate p53 and apoptosis.Therefore, treating cancer is not about killing cancer cells vigorously, but distorting the control mechanisms of cancer cells to push them past the dividing line between normal growth and apoptotic death. This explains why p53 is always a key player in determining how cells respond to anticancer therapies.As recently observed, cancer cells that lose p53 function are often more drug-resistant, apparently because it is difficult to coax cancer cells to commit suicide.These research results have great significance for the treatment of cancer. Soon, medical staff will be able to adjust the treatment plan according to the p53 gene in the patient's tumor cells.