The tumor suppressor gene p53 works as a checkpoint in the G, part of the cell cycle. If damaged DNA is detected, it stops the cycle and repairs it before the cycle can proceed. People with defective p53 are unable to repair the DNA, and if this damaged DNA is replicated, cells could become transformed to cancer cells.The opposite of cancer could be considered cell death. Cell death can occur in two fundamentally different manners. Cells can die through a pathological event, a process called necrosis. Necrotic cells are characterized by an abrupt increase in size and leaky membranes. No gene activation and no special input of ATP are necessary for cells to die in this manner. Apoptosis, or programmed cell death, is different from necrosis. Apoptosis occurs through activation of cell death genes, many of which have been identified in both vertebrates and invertebrates. Apoptosis causes the cell to shrink, with many plasma membrane blebs emerging from the cell. The nucleus is fragmented and the chromatin condenses. Neighboring cells often endocytose the apoptotic cell. The DNA is cleaved in a nonrandom manner, revealing a DNA ladder on a gel.While cancer and cell death appear to be opposites of each other, we are now recognizing that many chemotherapeutic treatments, such as radiation, that have been known for decades to kill cancer cells do so through activation of apoptosis. Thus, there is new hope and new energy devoted to understanding how apoptosis might be selectively activated in cancer cells-a strategy that is best accomplished once the biochemical basis of both cancer and apoptosis are fully appreciated.
The Cell Cycle and DNA Repair
All cells undergo a cell division cycle during which specific metabolic activities occur preparing the cell to split into two daughter cells. The cell cycle has been very well defined in eukaryotic cells and is divided into a number of cell cycle compartments. Go is that part of the cycle during which no cell division activities are under way. A cell in Go is regarded as differentiated and is often carrying out some type of function specific to that cell type, such as insulin secretion by pancreatic cells. When cells are triggered to enter the cell division cycle, they first enter G1, during which proteins critical to the cell division process are synthesized. Once cells have moved through G1. they enter DNA synthesis, or the S phase. During this phase cells replicate their DNA. Cells then enter the G2 compartment, during which more protein synthesis occurs. Finally the cells enter the most dramatic phase of the cell cycle, mitosis, or M. Mitosis is characterized by karyokinesis, the separation of the nucleus into two daughter nuclei, and cytokinesis, the microtubule and actin-mediated separation of the cytoplasm to form two new daughter cells. Mitosis can also be divided into prophase, metaphase, anaphase, and telophase according to the position of the chromatids and the degree of separation of the two new daughter cells.
The factors that control cell division have been studied actively in the past several years. Through two important independent lines of investigation, an M-phase promoting factor (or maturation-promoting factor) was discovered that triggers mitosis. This MPF leads to the dissolution of the nuclear envelope during mitosis. Further analysis revealed that MPF works through cyclins and a cyclin-dependent protein kinase. Briefly, cyclin B increases just prior to mitosis and combines with a cyclin-dependent protein kinase, forming an active MPF complex. This MPF phosphorylates lamin, among other substrates, and causes the dissolution of the nuclear envelope, triggering the initial phases of mitosis. At the end of mitotic prophase, polyubiquitination of the mitotic cyclin causes activation of the destruction box contained within the cyclin B molecule, causing its degradation. This decreases MPF activity to low levels until cyclin B is synthesized once again just prior to the next round of mitosis.
Further analysis has shown that eukaryotic cells have multiple cyclins and cyclin-dependent protein kinases that rise and fall in activity during different phases of the cell cycle. During the cell cycle it is critical that processes be in place to ensure that cell division occurs with near perfect fidelity There are several checkpoint controls in the eukaryotic cells. One checkpoint in G, detects DNA damage, and if mismatched bases are indeed present, the cell cycle stops in G, and sometimes the cell commits suicide through apoptosis. One important Gi checkpoint regulator protein is p53. People with deficient p53 are unable to block the replication of damaged DNA, and as a result mutations and cancer can occur. Other checkpoints occur in G2 that can detect unreplicated DNA and DNA damage. A final checkpoint occurs in mitosis, where if the mitotic spindle is not properly aligned, the cell cycle arrests in M. The microtubular destablizing agent colchicine arrests cells in M for this reason.DNA mispairing is somewhat of a paradox. While mismatching can lead to cancer if not detected by one of the checkpoint controls described earlier, mispaired bases are the basis of evolution. DNA mutation can occur through a number of mechanisms that include spontaneous mutation as well as radiation and chemically induced mutation. The types of DNA damage that occur include depurination, deamination, thymine dimerization, and production of reactive metabolites such as free radicals. There are several different enzymes that can repair DNA mutations. They include DNA polymerase, AP endonuclease, and DNA glycosylases. Inherited defects in repair enzymes can result in human disease states such as Xeroderma Pigmentosum, a malady characterized by increased sensitivity to ultraviolet light.In summary, a combination of internal cell cycle checkpoints coupled with a variety of DNA repair enzymes ensures that cell division occurs with the best possible fidelity. When one or more of these enzymes are either absent or not functioning properly, the chance of having a normal cell tranform to a cancer cell is increased.
Links about Research:
AMC Cancer Research Center - Non-profit institute dedicated to prevention located in Denver, Colorado. Includes current research, health information and other related resources.
Addenbrooke's NHS Trust - Academic and research resource center serving the East Anglia region of England.
Alberta Cancer Genetics Program - Information about this Canadian institutional research strategy and database which addresses the genetic susceptibility of cancer.
BC Cancer Agency - Provides a list of locations, patient information, services, information for health professionals, research and donations. Multiple sites in British Columbia, Canada.
British Columbia Cancer Research Center - Includes research information, publications, training opportunities and researcher profiles. Located in Vancouver, Canada.
Cancer Research Center of Hawaii - University affiliate unites researchers, modern equipment and technology to improve prevention and treatment. Located in Honolulu, Hawaii.
Cancer Research UK Clinical Centre at Leeds - Areas include clinical trials, psychosocial oncology, biological and immunotherapy work, genetics and screening.
Cancer Research and Biostatistics - Non-profit organization utilizes the application of biostatistical principles and methods. Located in Seattle, Washington.
Centre for Developmental Cancer Therapeutics - Consortium of hospitals and institutes based in Melbourne, Australia. Committed to furthering treatment and care techniques.
Fox Chase Cancer Center - Devoted to improving treatment through basic research, prevention research, cancer control and clinical medicine. Located in Philadelphia, Pennsylvania.
Fred Hutchinson Cancer Research Center - Information for scientific researchers, patients and educators. Located in Seattle, Washington.
In Silico Oncology Group - Development of computer models to optimize tumor therapy planning. Consortium includes the National Technical University of Athens in Zografos, Greece.
Irish Clinical Oncology Research Group - Information for physicians and patients about clinical research, with links to patient support groups. Located in Dublin, Ireland.
Laboratory of Immunology and Biology of Metastasis - Research, resources, publications, links and personnel from this division of the Department of Experimental Pathology at the University of Bologna, Italy.
Meharry Medical College/Vanderbilt-Ingram Cancer Center Partnership - Encourges research aimed at prevention and improved care in minority and underserved populations.
Rational Therapeutics Cancer Laboratories - Analysis of programmed cell death using the patient's own tumor cells to try to establish a treatment of choice.
San Antonio Cancer Institute - University affiliate and associate of the Cancer Therapy and Research Center in Texas. Includes genetics, drug development, prevention and control.
The NCI Center for Cancer Research - Conducts clinical trials at the National Institutes of Health in Bethesda, Maryland.
The Prostate Research Group - UK entity focused on the molecular and cellular basis of prostate cancer.
The Wistar Institute - Provides information about this NCI-designated Cancer Center and its orientation to research in basic science. Located in Philadelphia, Pennsylvania.
Walther Cancer Institute - Indianapolis, Indiana based organization which supports oncology projects in affiliation with several midwestern U.S. universities.