Chapter 14 Chapter 14 A Clock Without Hands: The Cell Cycle Clock

Every cell must have a well-functioning brain, that is to say, there must be a professional person sitting in the headquarters to receive information from various branches, weigh the pros and cons, and make prudent decisions.In reality, the range of decisions a cell's brain can make is limited—whether a cell grows, differentiates into a particular type of cell, dies.If individual cells make the wrong decisions about these crucial questions, the tightly-knit cell communities that make up our tissues can disintegrate into feral gangs, each of whom goes his own way, and chaos ensues.Although the decision-making content of this professional decision-making body is limited, the information on which the decision-making is based is very complex and comes from dozens of sources.These include external signals from growth factors, chemical exchange with neighboring cells, and "body" contact with neighboring cells and the protein matrix that surrounds them.In addition, there is a wealth of internal information, including regular reports on the health of the cell's DNA and the functioning of the cell's metabolic machinery.

Something must be done to condense, decompose, and process this hodgepodge of information.They must be aggregated into a single, final decision.All this can only be done by a supreme decision maker.Over the past 10 years, people have lifted the veil of this mysterious figure.It is the cell cycle clock hidden deep in the nucleus.It sits high behind the executive desk, listening to complex inputs, making difficult decisions, and calling the shots. The cell cycle clock orchestrates a cell's lifetime -- its cycles of growth and division.The active growth cycle of cells can be divided into four distinct phases.Cells will spend 6 to 8 hours duplicating DNA (S phase), 3 to 4 hours to prepare for cell division (G. phase), and then cells begin to divide, namely mitosis (M phase), this phase is only 1 hour.

The two daughter cells formed after division will spend 10 to 12 hours preparing for the next round of DNA replication, which is the G1 stage.Alternatively, G; stage cells may choose to exit the active growth cycle entirely and enter a period of dormant quiescence (G; stage) that can last for days, weeks, months, or even years.This "Rip Van Winkler" sleep is reversible. Once stimulated by the right signals, the cells wake up from their slumber and engage in a vigorous growth cycle. In just a few hours, they are running again. Shangsheng is alive and well. Actively growing human cells can do this for one round a day on a periodic track, but sometimes the cells pick up the pace considerably.The cell cycle clock manipulates cell fate by regulating the progression of cells on a circular racetrack through the life cycle, commonly referred to as the cell cycle.

In cancer cells, it is not surprising that the cell cycle clock is disrupted.By normal standards, the decisions made by the cancer cell's cycle clock are grossly inappropriate.Instead of being discreet, carefully weighing the pros and cons of growth and dormancy, the cell cycle clock makes rash decisions about growth.In fact, the cycle clock is running out of control.Since it is the master of the cell, the cell has to grow and divide infinitely. The status of the cycle clock in the cell signaling system highlights its leadership style.All the signals collected and processed by proto-oncogenes and tumor suppressor genes must sooner or later be aggregated to the cell cycle clock.Virtually all the wiring of the peripheral system extends into the nucleus, where it interfaces with the cell cycle clock.To understand the cycle clock is to understand cell growth, normal and cancerous states.Using the analogy of a clock must have gears and ratchets.Of course, these complex parts inside the cell are all composed of proteins, involving two protein components, one is cyclins, and the other is cyclin-dependent kinases (CDKs).Like all kinases, CDKs act by attaching phosphate groups to target proteins.Phosphorylation of a target protein alters the function of the target protein, putting it into a highly active or completely quiescent state.Because the kinase smears phosphates on many different target proteins, it can simultaneously alter different processes in the cell, sending high-strength signals throughout the cell's interior.

CDKs, which form the core components of the cell cycle clock, are controlled by their chaperones.Chaperones and CDKs go hand in hand, pointing to suitable target proteins for CDKs.They are cyclins—the CDK's guide dogs.Without the company of cyclins, a CDK is blind, unable to phosphorylate any of its targets. As cells go through different phases in their growth cycle, cyclins come and go.When it emerges, some cyclins direct their partners, CDKs, to phosphorylate targets that are critical to the cell's ability to replicate DNA; others direct phosphorylation of targets that lead to cell division. change.Without the cooperation of cyclins and CDKs, most of the cell's activities will stop, and the cell will enter the freezing phase-G.state.

The secret to the operation of the cell cycle clock lies not in the cyclins and chaperone proteins CDK.These two molecular components are merely unconscious cogs inside a clock.It is the controller above these two components that makes the wonderful periodic clock.By stimulating or inhibiting the cyclin-CDK joint action, it determines the operation of the clock. Almost all of the important decisions inside a normal cell about whether a cell grows or not are made during the G; phase of the growth cycle, in the hours after a cell divides and before the next round of DNA replication begins.During this time period, cells either continue to grow at full capacity, exit the growth cycle, or differentiate into another state, showing a new look, while giving up the possibility of dividing again.Most cells in the human body are in the "post-mitotic" state of differentiation.They are only engaged in a specific task, no longer grow and divide.Unfortunately, the body's brain cells belong to this fate.Tens of thousands of nerve cells die every day in the adult body, and because the remaining nerve cells lose their ability to reproduce forever, the nerve cells have no successors.

Within the cell cycle clock, several tumor suppressor proteins act as brake heads for different phases of the clock and have been intensively studied.For example, in the mid-to-late G; phase, the retinal glioma protein acts as a total brake.Unless it is phosphorylated by the appropriate cyclin-CDK combination, it flatly prevents the cell from proceeding.If it is not phosphorylated, the cell stalls in the G; phase and is forced out of the active growth cycle.Tumor cells, without glioma retinoma protein, go straight to DNA replication (S phase) without thinking about the factors that cause a normal, well-behaved cell to stop and consider its course of action

The p53 tumor suppressor protein also plays a role in the cell cycle clock mechanism.As mentioned earlier, when DNA is damaged, p53 levels rise. When p53 is activated, a second protein, p21, is produced; PZI then squeezes into all cyclin-CDK combination complexes, thereby blocking the cell cycle clock mechanism. Two other tumor suppressor proteins, H15 and K16, also function to inhibit the cell cycle clock.These two proteins are almost identical twins; either of them can block an important CDK that works during the G; phase of the growth cycle, thereby preventing cells from continuing to grow beyond the middle of the G; phase. Many functions of TGF card, a powerful growth inhibitory protein, are exerted through p15.We have mentioned that TGF binds to receptors on the cell surface.Once bound to TGF, the receptor signals the cell, causing a 30-fold surge in the P15 brake protein; then, a key CDK is blocked by P15 to shut down the cycle clock.

Patients with familial melanoma often inherit a defective form of the F16 gene.Without the ability to turn off the cell cycle clock under certain circumstances, the patient's cells would continue to grow inappropriately.Recent studies have shown that the P16 gene is also lost or inactivated in many other cancers.Some laboratories have reported that more than half of human tumors do not have p16 activity. All signals that promote cell proliferation must ultimately converge to the cell cycle clock.For example, signals stimulated by growth factors outside the cell are transmitted through the cytoplasm to the nucleus and affect the operation of the cycle clock.Most importantly, growth-stimulating signals induce the production of large amounts of cyclin D, a key kinetochore clock component.Cyclin D joins forces with a chaperone, CDK, to phosphorylate and inactivate retinal glioma brake proteins, allowing cells to advance to the next phase of the growth cycle.

Over the next 10 years, we will discuss how signals hitting the cell surface affect the components of the cell cycle clock, and how the clock processes these conflicting signals, makes decisions, and issues marching orders to the cell. figure out their details Fine-tuning the periodic clock: growth strategies of DNA tumor viruses Earlier in this book, we described a group of tumor viruses that can infect normal cells and turn these new hosts into cancerous cells.These retroviruses modify the stolen molecular genes, turning them into effective oncogenes.So they can induce cancer. RSV is the most notorious example of these oncogenes.As we have seen, an ancestor of RSV attacked a chicken cell, hijacked the cell's src proto-oncogene, and quickly transformed the gene into a potent oncogenic tool.The study of the src gene led us to discover the proto-oncogene, which then triggered a revolution in human understanding of the origin of cancer.

The successful pathways of other oncoviruses to carcinogenesis are quite different.They have spent millions of years fine-tuning their cancer genes. Impatient craftsmen like RSV carry their genes in the form of RNA (ribonucleic acid) molecules, while patient craftsmen use DNA as their genetic material. Both DNA and RNA molecules encode genetic information.Their structures are almost non-consistent, consisting of long strings of bases connected end to end.Cells choose the DNA molecule to store genetic information because it is extremely stable.However, short-lived viruses are less concerned about the long-term storage of genetic information, so some viruses use DNA, and some use RNA molecules as genetic databases. According to this standard, the virus can be divided into two kingdoms, and the two countries have clear boundaries between each other.They parasitize infected cells in very different ways.In addition, the strategies that RNA and DNA tumor viruses use to turn infected normal cells into cancer cells are quite different. The central agenda of DNA tumor viruses, like those of other viruses, is simple and clear: They just want to replicate as much as possible.Although a cell infected with a virus may occasionally become cancerous, the wish of the virus is only endless, with endless descendants, and cancer is just a by-product of their convenience. To successfully accomplish their goals, a DNA tumor virus must invade a cell, parasitize the host's DNA replication facility, and direct it to produce DNA instead of the cell's DNA-replicating enzymes.By taking advantage of the host cell's DNA replication facilities, these viruses can avoid the hassle and expense of assembling their own. This parasitic strategy also puts viruses in an awkward position, since most infectable cells in the human body are always in a quiescent state outside of active growth cycles for periods of time.Because quiescent cells shut down many of their growth facilities, including DNA replication, they are stingy hosts for infectious DNA tumor viruses.The immediate task for viruses is to convince their new hosts to be generous and welcoming. DNA tumor viruses have solved this problem by virtue of their sheer ingenuity.After a virus invades a host cell, it coaxes its host out of a quiescent state and into an active growth cycle.The awakened host cell now activates the growth machinery, including the once-inactivated DNA replication tools, for use in the growth cycle.But the virus has its own wishful thinking: it preemptively prevents the normal use of the host cell's DNA replication facilities and uses it to replicate its own viral DNA.The replicated viral DNA is combined into new progeny virus particles, which leave the parasitic cell and complete the viral life cycle.Often the host cell is also forced to commit suicide, falling prey to the virus' tricks. The crux of the trick lies in the mechanism that DNA tumor viruses use to activate dormant cells.One of the most interesting strategies came up with the human papillomavirus (HPV). HPV occurs in more than 90% of cervical cancer cells. The strong link between HPV infection and cervical cancer is not just a coincidence.Cervical cancer epidemiology has long considered the category of infectious disease: the more sexual partners a woman has, the higher the incidence of cervical cancer.There is no doubt that HPV infection is the direct cause of cancer. There are dozens of types of HPV, some of which only cause common skin warts.Several types of HPV grow well in the epithelial layer of the cervix.Cervical cancer occasionally occurs after decades of chronic HPV infection in the cervical epithelium.However, the vast majority of women infected with HPV do not develop cancer.Although HPV is involved in most cervical cancers, HPV alone is obviously not enough.In addition to initial viral infection, cervical epithelial cells must undergo several other low-probability events before they become significantly cancerous. HPV uses its E7 viral oncogene to induce the growth of infected cervical epithelial cells. A certain protein product produced by the E7 gene directly interferes with the growth control facility of the host cell by inhibiting the key retinal glioma protein, so that the key braking device of the host cell fails, and the cell cycle clock cannot be turned off, nor can growth be stopped.Infected cells untether themselves into a state of active growth, becoming generous hosts for viral growth. As mentioned earlier, cells often respond to viral infection by apoptosis.Inactivation of the cellular retinal glioma protein also causes apoptosis.This response is usually initiated rapidly, depriving HPV of an independent host on which to multiply and threatening the HPV growth program.Thus, **V makes a second protein, *6, which disables the host cell's 53-producing protein, thereby blocking the apoptotic response. By inactivating both the retinal glioma protein and the p53 tumor suppressor protein, HPV removes two major stumbling blocks on the way forward, allowing it to grow and reproduce wantonly in host cells. To speed up their own growth, other DNA tumor viruses do the same.One monkey virus, called SV40, makes only one oncoprotein called the T antigen, which binds and sequesters p53 and the retinal glioma protein in infected cells.Certain strains of human adenoviruses are particularly interesting because of their different effects: in natural host species, humans, they cause common upper respiratory tract infections, and in unnatural host species, such as hamsters and rats, they cause tumors .Like other DNA tumor viruses, these adenoviruses also produce oncoproteins, inactivate the retinal glioma protein and the P53 tumor suppressor protein, help the infected host cells to break free from growth constraints, and turn them into absolute musts for virus replication. good environment. To deal with host apoptosis, adenovirus has another hand.Another oncogene it carries, similar to the cellular BC2 oncogene, blocks the apoptotic response.This ensures that the host cell does not die young, long enough for the virus to complete the entire growth cycle and replication cycle to reproduce. Perhaps because adenoviruses are so good at multiplying and killing infected human cells, adenoviruses are not associated with cancer in humans.In rodents, however, the adenovirus tricked infected cells into growing as usual, beginning a round of growth and replication.However, in these unnatural host cells, the virus cannot then successfully complete the round of viral replication and cell killing.These infected rodent cells were left alive, along with the viral oncogenes in the cells that effectively stimulated growth.That's how they become tumor cells In the West, only a small percentage of cancers are caused by viral infections.But over the past 20 years, studying the life cycle of DNA tumor viruses, especially SV40 and adenoviruses, has opened a window for scientists to study the inner workings of the cell cycle clock, which seems to be compromised by all human cancers. cell cycle clock.