Author: Tang Cristina
Institution: Biochemistry
Date: May 2002
The human body can be thought of as a small laboratory (weighing no more than ~3 kg at birth) where millions of chemical reactions can take place at the same time, in the right order, and in the right compartment. It is also probably the only "machine" that knows to save fuel when fed in excess and to bring out the reserves when starved, one that can protect itself when attacked by viruses and bacteria, one capable of adjusting and withstanding changes of weather and most importantly, one that is able to learn, think, and create on its own. The human body is a highly integrated and organized system, able to respond to a wide range of stimuli in order to perform all the functions that are vital to our survival. Moreover, since errors and malfunctions in this "organic factory" can have damaging results, ranging from discomfort to life-threatening illnesses, many reactions and processes that take place within our cells are under very tight control.
An example of one of the many complicated-yet-elegant processes that continuously occur in our bodies is the cell division cycle. As you read this sentence, many of the cells in your body are dividing into two. However, behind this seemingly simple step is a complicated series of reactions and changes, such as DNA replication and protein synthesis, which involve a dazzling array of proteins working in concert to achieve a common goal.
The cell division cycle is generally divided into four phases. In normal cells, progress from one phase to the next is always strictly controlled at so-called "checkpoints." Checkpoints can be considered safety measures for the cell, preventing the control system from dictating the start of another cell cycle event before the previous one has finished, or before any damage to the cell has been properly repaired. In addition to internal signals provided by the checkpoints, completion of the cell division cycle is also dependent upon external cues. When cell division is unregulated and independent of external cues, it has the potential of leading to one of the most devastating diseases that afflicts almost one in five people in first-world countries: cancer.
The cell division cycle has been divided into the G1 (growth) phase, followed by the S (synthesis) phase, G2 phase (second growth), and the M (mitotic) phase. Cells that are not dividing (quiescent) are said to be in the G0 phase. When cells receive external cues (i.e., growth factors released by neighboring cells) to initiate division, they move from the quiescent state into the G1 phase. In the G1 phase, cells prepare for division by producing more proteins. In the S phase, cells replicate their DNA, creating two identical copies so that each daughter cell can each inherit an exact copy. In G2, cells continue to grow and synthesize all the proteins the daughter cells will need after division. And finally, in the M phase, the cell separates its DNA and divides into two.
All cells must accurately replicate and segregate their chromosomes during cell division. To accomplish these tasks in an ordered and sequential manner, all the events related to cell division must be coordinated throughout the duration of the cycle. For example, if a cell divides before it has reached a certain size, then the daughter cells would become smaller with every subsequent division. How do cells regulate the processes of the division cycle? The answer lies within a set of interacting proteins that form the cell cycle control system. This system of proteins, as the "chief commander" of the cycle, directs and coordinates other proteins involved in particular tasks such as in DNA replication. However, in spite of its "power" to act on other proteins, the control system must still follow feedback signals coming from the cell cycle itself. There are other proteins in the cell cycle involved in surveillance control mechanisms. These proteins can stop or delay the progress of the control system at the cycle checkpoints. In fact, several defects or syndromes that lead to increased susceptibility of developing cancer are the result of the loss or inactivation of a gene encoding a protein in the surveillance system.
The control system of the cell cycle is based on two families of proteins: the cyclins and the cyclin-dependent kinases (Cdk). Cdks induce other proteins to perform their functions by phosphorylating (adding a phosphate group) key amino acid residues, and cyclins bind to Cdks to control their ability to phosphorylate those target proteins.
Many proteins are involved in the surveillance system. There are several ways by which they can delay or terminate the progress of the cell cycle. Some proteins, for example, can promote the rapid degradation of cyclins and others can prevent the entry of Cdk-cyclin complexes into the cell compartments where they are needed to promote cell cycle progression. The first checkpoint a cell encounters before entry into the cycle is at the transition between G0 and G1. A protein suspected to be involved at this point is encoded by the retinoblastoma (Rb) gene. The Rb protein inhibits the passage of the cell past the "start" point of the cycle by shutting off the transcription of genes required for cell division and sequestering the proteins that regulate DNA replication. The importance of this gene in the regulation of cell division is made evident by the fact that many common types of cancer, such as lung, breast, and bladder cancer, are missing both functional copies of the Rb gene.
Once the cell has entered G1, it can continue unchecked until the beginning of the S phase. The G1/S metaphase then ensures that the DNA is intact before replication. The protein p53 stops progression of the cell cycle when even the smallest DNA damage occurs. This protein is produced in greater quantities when the cell is exposed to DNA-damaging agents (e.g., UV radiation) and induces the synthesis of another protein that inhibits the function of the Cdk-cyclin complex. In humans, absence of one good copy of this gene is associated with Li-Fraumeni syndrome, which is the characterized by the propensity to develop tumors in several tissues. This predisposition to cancer is related to the cell's increased chances of producing daughter cells that carry mutations that can lead to the formation of tumors, since without control from p53, the cell is more likely to progress from the G1 to S phase even when DNA is damaged.
More cell cycle checkpoints can be found at the G2/M transition and within the M phase. At the G2/M checkpoint, for example, failure to complete DNA replication causes specific proteins to inhibit the action of the Cdk-cyclin complex by preventing their entry into the nucleus. Within the M phase, control mechanisms ensure that the cell does not divide until all the chromosomes have moved toward opposite poles of the cell.
Because of the large network of proteins involved in cell cycle progression and regulation, we are still far from understanding the details of its functioning. However, intense cancer research has uncovered many genes and the roles they play in this cycle. Hopefully, through a gradual understanding of the mechanisms underlying this complex system, we can find the long-awaited cure for this disease.
Suggested Reading
Hunter T. and J. Pines. "Cyclins and Cancer. II: Cyclin D and CDK inhibitors come of age". Cell 79(1994): 573-582
Hatakeyama M and R.A. Weinberg. "The role of RB in cell cycle control." Prog Cell Cycle Res.1(1995): 9-19
Hartwell L.H. and T.A. Weinert.. "Checkpoints: controls that ensure the order of cell cycle events". Science. 246(1989): 629-633
Kastan M.B., et. al. "Participation of p53 protein in the cellular response to DNA damage". Cancer Res. 51(1991): 6304-6311
Srivastava S., et.al . "Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome". Nature. 348(1990): 747-749
Evan G. and T. Littlewood. "A matter of life and cell death". Science. 281(1998): 1317-1322.