Biology

Review part 3
(by some wiki material, Essential Cell Biology, and personal adds)

(May the force be with us)

Cellular senescence and medical implication Cellular senescence is the phenomenon by which normal diploid cells lose the ability to divide, normally after about 50 cell divisions in vitro. Some cells become senescent after fewer replications cycles as a result of DNA double strand breaks, toxins, etc. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit in honour of Dr. Leonard Hayflick who was the first to publish this information in 1965. In response to DNA damage (including shortened telomeres), cells either age or self-destruct (apoptosis, programmed cell death) if the damage cannot be easily repaired. In this 'cellular suicide', the death of one cell, or more, may benefit the organism as a whole. For example, in plants the death of the water- conducting xylem cells (tracheids and vessel elements) allows the cells to function more efficiently and so deliver water to the upper parts of a plant. The ones that do not self- destruct remain until destroyed by outside forces.

As noted above, senescence is not universal, and senescence is not observed in single-celled organisms that reproduce through the process of cellular mitosis. Moreover, cellular senescence is not observed in several organisms, including perennial plants, sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis; i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted

above) it is widely believed that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued. Lately, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells do not age and are, therefore, described as being "biologically immortal". It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and, therefore, stop or reverse aging, effectively making the entire organism potentially immortal. The length of the telomere strand has senescence effects, telomere shortening activate extensive alterations in alternative RNA splicing that produce senescence toxins such as progerin that degrades the tissue and makes it more susceptible to failure. Cancer cells are usually immortal. In about 85% of tumors, this evasion of cellular senescence is the result of up- activation of their telomerase genes. This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk. Whether cell senescence plays any role in organismal aging is at present unknown, and is an active area of investigation. Mouse mutants lacking telomerase do not immediately show accelerated aging.

Cellular Death, Necrosis and Apoptosis Necrosis is the premature death of cells and living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal. Cells that die due to necrosis do not usually send the same chemical signals to the immune system that cells undergoing apoptosis do. This prevents nearby phagocytes from locating and engulfing the dead cells, leading to a build-up of dead tissue and cell debris at or near the site of the cell death. For this reason, it is often necessary to remove necrotic tissue surgically, a process known as debridement. Causes of necrosis: Cellular necrosis can be induced by a number of external sources, including injury, infection, cancer, infarction, poisons, ROS(Reactive Oxygen Species), and inflammation. For example, an infarction (blockage of blood flow to muscular tissue) causes necrosis of muscle tissue due to lack of oxygen to the affected cell, such as occurs in a myocardial infarction -- a heart attack. Certain spider (brown recluse) and snake (rattlesnake, Bothrops) venoms can cause necrosis of the tissue near the bite wound, as can a Group A streptococcus infection (one of the "flesh-eating" bacteria). Necrotic tissue does not undergo the same chemical reactions that normally dying apoptotic tissue does. The sudden failure of one part of the cell triggers a cascade of events. In addition to the lack of chemical signals to the immune system, cells undergoing necrosis can release harmful chemicals into the surrounding tissue. In particular, cells contain small organelles called lysosomes, which are capable of digesting cellular material. Damage to the

lysosome membrane can trigger release of the contained enzymes, destroying other parts of the cell. Worse, when these enzymes are released from the non-dead cell, they can trigger a chain reaction of further cell death. If a sufficient amount of contiguous tissue necrotizes, it is termed gangrene. Proper care and treatment of wounds or animal bites plays a key role in preventing this type of widespread necrosis. During a surgical biopsy, this necrosis chain- reaction is halted by fixation or freezing.[citation needed] Necrosis typically begins with cell swelling, chromatin digestion, and disruption of the plasma membrane and organelle membranes. Late necrosis is characterized by extensive DNA hydrolysis, vacuolation of the endoplasmic reticulum, organelle breakdown, and cell lysis. The release of intracellular content after plasma membrane rupture is the cause of inflammation in necrosis. Apoptosis (key features) Is a form of cellular death triggered by activation of death receptors, withdrawal of survival factors, or as a result of DNA damage Apoptosis involves the orderly dismantling (making in pieces) of a dying cells contents Proteases called caspases are key mediators of apoptosis. Initiator caspases can be activated in several ways, including through the release of cytochrome c from mitochondria. Initiator caspases activate executioner caspases, which in turn activate other apoptosis proteins. Step by step induction of apoptosis: 1. Cell death signals, such as ligands on the surface of a cytotoxic T lymphocyte, can lead to apoptosis. 2. Ligand binds to a death receptor on the surface of a target cell. Binding causes clustering of receptors and

3. 4. 5. 6.

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recruitment od adaptor proteins in the target cell, resulting in clustering of initiator procaspase-8 protein Initiator caspases then become activated The initiator caspases in turn activate the executioner caspase-3, a key initiator of apoptosis When survival factors are no longer present Death-promoting proteins accumulate, counterbalancing anti-apoptotic proteins at the mitochondrial outer membrane causing the release of cytochrome c This last forms a complex with other proteins, resulting in activation of an initiator caspase-9 The initiator caspase in turn activates the executioners caspase-3, triggering apoptosis DNA damage can also lead to apoptosis through the activity of the protein p53

Medical implication (thx wiki) Defective apoptotic pathways The many different types of apoptotic pathways contain a multitude of different biochemical components, many of them not yet understood.[34] As a pathway is more or less sequential in nature, it is a victim of causality; removing or modifying one component leads to an effect in another. In a living organism this can have disastrous effects, often in the form of disease or disorder. A discussion of every disease caused by modification of the various apoptotic pathways would be impractical, but the concept overlying each one is the same: the normal functioning of the pathway has been disrupted in such a way as to impair the ability of the cell to undergo normal apoptosis. This results in a cell that lives past its "use-by-date" and is able to replicate and pass on any faulty machinery to its progeny, increasing the likelihood of the cell becoming cancerous or diseased.

Inhibition of Apoptosis Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. It was originally believed that the associated accumulation of cells was due to an increase in cellular proliferation, but it is now known that it is also due to a decrease in cell death. The most common of these diseases is cancer, the disease of excessive cellular proliferation, which is oftentimes characterized by an overexpression of IAP family members. As a result, the malignant cells experience an abnormal response to apoptosis induction: cycle regulating genes (such as p53, ras or c-myc) are mutated or inactivated in diseased cells, and further genes (such as bcl- 2) also modify their expression in tumors. Hyperactive Apoptosis On the other hand, loss of control of cell death (resulting in excess apoptosis) can lead to neurodegenerative diseases, hematologic diseases, and tissue damage. The progression of HIV is directly linked to excess, unregulated apoptosis. In a healthy individual, the number of CD4+ lymphocytes is in balance with the cells generated by the bone marrow; however, in HIV-positive patients, this balance is lost due to an inability of the bone marrow to regenerate CD4+ cells. In the case of HIV, CD4+ lymphocytes die at an accelerated rate through uncontrolled apoptosis, The progression of the human immunodeficiency virus infection into AIDS is primarily due to the depletion of CD4+ T-helper lymphocytes in a manner that is too rapid for the body's bone marrow to replenish the cells, leading to a compromised immune system. Viruses can trigger apoptosis of infected cells via a range of mechanisms including: Receptor binding Activation of protein kinase R (PKR)

 Interaction with p53 Expression of viral proteins coupled to MHC proteins on the surface of the infected cell, allowing recognition by cells of the immune system (such as Natural Killer and cytotoxic T cells) that then induce the infected cell to undergo apoptosis

Key points of the biology of Cancer

Cancer cells proliferate in an uncontrolled way and are capable of spreading by invasion and metastasis The balance between cell division and differentiation is disrupted in cancers, leading to a progressive increase in the number of dividing cells Cancer cells are anchorage-independent, exhibit a decreased susceptibility to density-dependent inhibition of growth, and are capable to replenish their telomeres Sustained tumors growth requires a network of blood vessels whose growth is triggered by an increased production of angiogenesis activators and a decreased production of angiogenesis inhibitors Cancer cells invade surrounding tissues, enter the circulatory system, and metastasize to distant sites. Invasion is facilitated by decreased cell-cell adhesion, increased motility, and secretion of proteases that degrade the extracellular matrix and basal lamina. Only a tiny fraction of the cancer cells that enter bloodstream establish successful metastases Sites of metastases are determined by the location of the first capillary bed as well as by organ-specific conditions that influence cancer cell growth

Main causes of cancer: Some cancers are caused by certain kinds of chemicals, including those found in tobacco smoke. Chemicals cause cancer through a multistep process involving initiation, promotion, and tumor progression. Initiation is based on DNA mutation, whereas promotion involves a prolonged period of cell proliferation accompanied by selection of cells exhibiting enhaced growth properties. During tumor progression, additional mutations as well as epigenetic changes in gene expression produce cells with increasingly aberrant traits Cancer can also be caused by ionizing radiation and by sunlight, both which trigger DNA mutations, as well as by certain viruses, bacteria and parasites Some cancer-causing viruses act by directly triggering cell proliferation, either through the action of viral genes or by altering the behavior of cellular genes. Other viruses and infectious agents create tissue destruction that indirectly stimulates cell proliferation under conditions in which DNA damage is likely Oncogenes and tumor suppressor genes: Oncogenes are genes whose presence can cause cancer. Although oncogenes are sometimes brought into cells by viruses, more often they arise from normal cellular genes (proto-oncogenes) by point mutation. Gene amplification. Chromosomal translocation, local DNA rearrangements, or insertional mutagenesis Many of the proteins produced by oncogenes are signaling pathway components, such as growth factors, receptors, plasma membrane GTP-binding proteins, non-receptors protein kinases, transcription factors, and cell cycle or cell death regulators. Oncogenes code

for abnormal forms or excessive quantities of such proteins, thereby leading to excessive cell proliferation Tumor suppressor genes are genes whose loss or inactivation can lead to cancer. Susceptibility to cancer is increased in people who inherit defective tumor suppressor genes The genetic instability of cancer cells facilitates the acquisition of multiple mutations