The CDK "Engines" Are Controlled by Both Throttle (Oncogene) and Brake (Tumor Suppressor) Controls
The CDK-cyclin pairs are controlled by both stimulatory and inhibitory pathways, analogous to an automobile engine controlled by throttle and brake mechanisms. The throttle mechanisms are largely the result of the cell’s environmental inputs.
That is, various environmental cues, both soluble signal molecules and insoluble molecules found in tissue, are required for cells to divide. However, the pathways sending inhibitory signals to the cell cycle, the “brakes” for cell division, are largely internal and are activated by damage or stress to the cell. In general, these inhibitory signals are like the safety interlocks on an automobile. Just as one cannot start a car in gear, so the cell should not divide if DNA synthesis has not exactly duplicated all the genes and chromosomes, or if something is wrong with the mitotic spindle.The environmental stimulatory signals for cell division can be as simple and nonspecific as availability of nutrients, to the extent that cells only divide when they have approximately doubled in size through synthetic growth. However, two more specific stimulators of the cell cycle are primarily implicated in cancer. One is the response to soluble growth factors found in the circulation and in the extracellular fluid surrounding cells (see Chapter 1). Growth factors are proteins secreted by a variety of other cell types that are required for the division, and indeed survival, of normal, noncancerous cells. Cancer cells, however, can divide and survive with little or no stimulation from growth factors because of the acquired ability to synthesize growth factors of their own, or the activation of downstream elements in the signaling pathway.
The second stimulatory pathway of general importance in cancer is cell attachment. The cells of multicellular organisms must be tightly attached to one another and to their surrounding matrix, similar to tendon; otherwise we would be jelly, juice, and bubbles on the floor.
Also, however, attachment of cells to their surroundings is a source of specific and complex information to the physiology of the cell. One of the most important such messages is a “permissive” signal to divide. Normal cells must be anchored to some substrate in order to respond to other signals to divide. That is, most normal animal cells show anchorage dependence of growth. For this reason, vertebrate cells in culture are grown on the surface of a dish or flask, not in suspension the way bacteria are cultured. Once again, cancer cells have lost this normal restriction on proliferation, and many cancer cells can divide and survive in suspension. The common lest for the absence of anchorage dependence is growth in soft agar: cancer cells will, but normal cells will not, divide and form colonies when suspended in soft agar. Thus, cancer cells can survive unattached while riding the circulation to relocate in a different tissue than that of the original tumor. In this way, cancer is able to spread through the body, a process called metastasis, which is ultimately the cause of death in most cases of cancer.The uRube Goldberg” pathways that underlie the proliferative signals of growth factors and adhesion are similar and intersect. These “throttle” contraptions begin with a soluble signal binding to a growth factor receptor and a “solid- state” signal about attachment to the surrounding tissue. However, both pathways quickly converge on the same stimulation pathway for conserved cell division. These stimulatory pathways are driven by proteins that were originally identified as being encoded by genes in viruses that caused cancer in animals. Thus these were named oncogenes, literally “cancer genes.” A major breakthrough came with the discovery that these oncogenes were actually derived from the host genome, not genes normally encoded in the virus. That is, viruses had stolen cell cycle control genes from their animal host cell. Being viruses, they did not take good care of the animal cell cycle genes they stole.
The stolen genes mutated into deranged cell cycle regulators. Subsequently, the same mutant genes that were found in viruses were found to explain many spontaneous cancers in humans and in the long-used experimental tumors of mice. The finding that cancer was caused by abnormal host genes helped confirm that cancer was a somatic genetic disease due to mutations in the tumor cells.Further analysis revealed that these oncogenes often encode normal stimulators of the cell cycle, and the mutations involved had the effect of permanently activating an element in the cell cycle pathway. You can see how this would work based on the Rube Goldberg cartoon of Figure 1-13. Note that all the elements in the garage door opener are stimulatory; if any one turns “on,” a signal is sent “downstream” to cause the garage door to open. If the fish tank of the cartoon were to “mutate” by developing a leak, an “on” signal would be sent downstream of the fish tank, regardless of whether a car had pulled into the driveway. So it is with the oncogene elements controlling the cell cycle. If one of the elements mutates to turn itself “on,” that is, acquired & gain-of-function mutation, it will stimulate cell division and contribute to cancer. To return to the automobile analogy, oncogenes represent a stuck throttle or accelerator pedal. The normal, well-behaved versions of the oncogene (a watertight fish tank before the bullet, Figure 1-13) are called proto-oncogenes. Thus, strictly speaking, “oncogenes” have their normal equivalent as “protooncogenes.” However, given this awkward usage, increasingly the normal versions are also informally called oncogenes, and it is usually clear from the context whether the mutant or normal version is being discussed. The molecules and molecular events of the oncogene pathway (also called the “growth factor” or MAP kinase pathway) are discussed later.
The mechanisms to stop the cell cycle, the “brakes,” are called checkpoints. Progress through the cell cycle depends on appropriate conditions being reached within the cell before a “decision” is made to go ahead with division.
The first such checkpoint occurs before S phase. During Gl, the cell checks itself over particularly with respect to DNA damage. The cell has sophisticated pathways to detect and repair DNA damage, such as mismatched bases detected in the double helix. For needed repairs to take place, however, DNA synthesis is delayed; the checkpoint is “engaged.” If the DNA is properly repaired, the checkpoint is disengaged, and after the delay, the cell goes ahead into S phase. However, if the DNA damage cannot be repaired, the checkpoint machinery is supposed to signal a more serious consequence. If the checkpoint is not disengaged after about a day, the cell “commits suicide.” Thus the checkpoint (or braking machinery) is tied into both the CDK engines and the processes of cell suicide, as described later. Similarly, the second checkpoint is in mitosis and checks for proper mitotic spindle assembly and correct chromosome alignment. Here again, if damage is detected, there are repair mechanisms, and a properly repaired cell will go into M phase after a delay for repair. If no repair can be made, the cell commits suicide.The molecules and their interactions that underlie both oncogene (“throttle”) pathways and checkpoint (“brake”) pathways are now covered in greater detail, beginning with the role of growth factors.