Cell Death - Microtubules in Apoptosis - Assignment Example

Lecturer “Cell Death” All organism are made up of millions of cells that perform different functions under different conditions in their daily activities. These cells are subject to the ‘use – disuse’ theory and as such, they die after some time. The cells may die non-accidentally after they have completed a given number of division cycles. The Hayflick limit puts the estimate of the number of cycles at about 60. The cells could as well die at an earlier stage if so programmed like in the experiment case study where the reindeer cultured cells die after being exposed to Grinch or in digit separation in morphogenesis. This programmed cell death is called apoptosis; where cells deliberately destroy themselves. The events around the death are controlled by the nuclear genes. It begins with the breaking of the chromosomal DNA into fragments then the breakdown of the nucleus. Ultimately after time the cell shrinks and is fed on by the neighboring cells and macrophages. Cells that are damaged for some reason like DNA alteration or infection undergo programmed death. The process removes lethal cells which could lead to undesired mutation or viral spread. The cell might as well die for reasons like starvation, trauma, or asphyxiate. (Geoffrey and Robert, 97 ) Programmed cell death plays a very major role in maintaining the life and health of organisms. It is a normal part of embryonic development. For instance, the fingers and toes of a human are webbed when in the embryonic stage. Through cell death, the webbing is removed through apoptosis. The immune and nervous systems are also largely developed through the same process. (Wayne, 24) The process of apoptosis involves a variety of intra and extra cellular stimuli. When it is induced by extra-cellular factors, it is triggered by cell surface death receptors. These death receptors have cytoplasmic death domains (FADD and TRADD). They are typified by the tumor necrosis receptor superfamily which includes tumor necrosis factor receptor 1 (TNFR-1), TNF related apoptosis – inducing ligand recptor 1 (TRAILR-1), death receptor 3ectodermal dysplasia receptor (EDAR), nerve growth receptor and the cytotoxic T-cell proteins like perforin and granzyme-B. The FAS receptor is found on the surface of the cell (on the chromosome) and it leads to programmed cell death. Apoptosis uses it as a pathway. It also uses the mitochondrial pathway (Geoffrey and Cooper, 46) Apoptosis is driven by the impetus of enzymes from the regulated family proteolytic enzymes called caspases. Caspases are made up of upstream (initiator) caspases which are normally activated by death receptor signalosomes, casase 9, activated by the mitochondrial cytochrome derived apoptosome; downstream caspases (effectors) which cleave the involved proteins. Interaction with death receptor cytoplasmic death inducing signaling complexes that contain FAS-associating death domain activates caspases 2, 8 and 10. The receptors are activated by ligands involved in signaling cell death hence supporting cell selection, homeostasis, and morphogenesis and host defense (Carlo, 16) Death receptor ligands include Fas ligand, tumor necrosis factor alpha, NF-related apoptosis inducing ligand, TNF-related weak inducer of apoptosis, TNF-related molecule 1 and nerve growth factor. The ligand is a homotrimetic type II transmembrane protein of the TNF family. It induces apoptosis through trimetization hence playing an important role in the regulation of immune system. It also has a role in the progression of cancer. It is the Fas ligand that forms the death inducing signaling complex (DISC). Caspase-8 is released from DISC to the cytosol and it cleaves the other effector caspases. This leads to DNA degradation, membrane blebbing and other events that are associated with apoptosis. It is suggested that the extrinsic Fas pathway on its own can induce apoptosis in certain cell types. These cells are dubbed Type 1 cells and are characterized by the inability of the anti-apoptotic members of the Bcl-2 family to protect from the threat. (Esteve et al, 29) The Bcl-2 family is a group of twenty five evolutionary related proteins which govern the permeabilization of the mitochondrial outer membrane. They can be pro-apoptotic or anti-apoptotic. Bax,BAD,Bak and Bok are examples of pro-apoptotic proteins while Bcl-xL and Bcl-w are examples of anti-apoptotic proteins. The family achieves its pro/anti-apoptotic effect through activation or inactivation of an inner mitochondrial permeability transition pore. The pro-apoptotic family members may induce the release of cytochrome c into cytosol as the anti-apoptotic members inhibit it. Once there, it activates caspase-9 and caspase-3 leading to apoptosis. Similarly, there is a theory that suggests that Rho proteins help in the activation of Bcl-2, Mcl-1 proteins and increases the levels of proteins of pro-apoptotic Bid but do not affect Bax or the levels of FLIP. Rho is said to induce caspase 9 and 3 dependent apoptosis of cultured cells. The family share the four characteristic domains of homoxology (BH). The Bh domains are crucial to the proteins for function and their deletion through molecular cloning directly affects survival/apoptosis rates. The family is made of transmembrane domains that have a general structure of the hydrophobic helix. It is surrounded by amphipathic helicies. Most of the action for this family is on the mitochondrial membrane (Wayne, 57) Apoptosis is also affected by cytochrome. Cytochromes are membrane bound homoproteins containing the heme groups and carry out electron transport. They are mainly within monomeric proteins e.g. cytochrome c family. They carry out oxidation and reduction in a sequence for efficiency. Cytochrome c is a protein that is very soluble at 100g/l. It is involved in the initiation of apoptosis (Geoffrey and Cooper, 77) Similarly important in apoptosis are the microtubules. They are part of the cytoskeleton. They grow to 25 micrometers with a 25 mm diameter and are very dynamic. They shape the cell and provide channels of intracellular transport among other processes. Of importance to apoptosis is the fact that they have proteins that bind to them. These include the motor proteins kinesin and dynein. Microtubule targeting agents (MTA) modify the cytoskeleton by affecting the microtubule. They induce cell arrest hence apoptosis. (Esteve` et al, 33) Normal cells undergo the programmed apoptotic death. However, those cells meant to die can survive and proliferate due to the action of the oncogene gene. The genes cause cancer due to the high rate of multiplication and mutation. As a result, cancer drugs target the oncogene proteins. Within the body are the anti-oncogenes, also called tumor suppressor genes. They protect the cell from the cancer resultant genes. The anti-oncogenes have repressive effects on the regulation of cell cycle to promote apoptosis. Apart from repressing the genes, they also couple the cell cycle to DNA damage, initiate apoptosis where the damaged cell can not be repaired and also act as tumor suppressors (Carlo, 6) Finally, the G protein coupled receptors are a large family of receptors which sense molecules that are outside the cell and prepare it for cellular responses. Due to passing through the cell membrane, they are called transmembrane receptors. The ligands that bind them include the light-sensitive compounds, ordors, neurotransmitters and hormones. The G-protein it is noteworthy is the target of approximately 40% of modern medicine. They are involved in tumor growth and metastasis, cell density sensing, regulation of immune system transmission and the sense of smell (Gerald, 37) Works Cited Carlo M. Croce, M.D., (2008), The New England Journal of Medicine; Molecular Origins of Cancer Oncogenes and Cancer, Massachusetts Medical Society Estevez, M.A., Carre, M., Braguer D., (2007), Microtubules in Apoptosis Induction: Are They Necessary? US National Library of Medicine National Institutes of Health Gerald Litwack, (1997) Cell Death Proteins: Advances in Research and Applications Cell Death Protein, Academic Press Geoffrey M. Cooper, Robert E., (2009) Hausman, the Cell: A Molecular Approach ASM Press Wayne M. Becker, (1986), The world of the cell, Benjamin/Cummings Publishing Co Read More