Structural Biochemistry/Cell Signaling Pathways/Problems in Signaling that cause Cancer

Cancer can occur in many different ways. The overall idea of cancer is that a cell grows and divides erratically on its own, even without a cell signal, resulting in uncontrolled cell growth. The cell cannot die either, causing a build up of excess cells in a certain area c. Such an excess cells is known as a tumor. Cancer is due to multiple cell signaling breakdown. Uncontrolled cell communication also leads to the incorporation of the blood vessels to grow into the tumor, taking up a majority of the nutrients and causing the tumor to grow even larger. More cell signaling allows the cancerous cells to move to other parts of the body. Many mechanisms maintain healthy cell growth. External signals direct cell division, cell-to-cell signaling occurs, and enzymes can repair damaged DNA. Apoptosis is programmed cell death, which is needed to maintain the shape of the organism. When a cell is not repairable, it signals its own death.

When cell communication breaks down, uncontrolled cell growth can occur and often lead to cancer. Cancer often begins when a cell gains the ability to grow and divide even in the absence of a signal from the environment. Ordinarily, the unregulated growth triggers a signal for self destruction, otherwise known as apoptosis. However, when a cell also loses the ability to respond to self-destruct signals, the cell divides uncontrollably and, consequently, forms a tumor.

Overview of the Signal Transduction Pathway

The signal transduction pathway is a chain of events that converts the message of a molecule present in the extracellular environment to a physiological response.

The signal transduction pathway is illustrative of a molecular circuit.

Primary messenger release is triggered by a stimulus such as a wound or food.
The primary messenger, also referred to as a ligand, is received by a receptor, forming a receptor-ligand complex. Proteins that span the cell membrane act as receptors that bind the ligands, transmitting extracellular information from the environment to the cell's interior.
Smaller molecules inside the cell known as secondary messengers relay the information from the protein receptor. Examples of secondary messengers are GMP and calcium ion. Some undesired effects of secondary molecules are the freedom of secondary messengers to diffuse within the cell, which then influences other process within the cell. "Cross talk" alters the concentration of common secondary messengers when multiple receptor signals are processed, and a single activated receptor can yield a large intracellular response through the activation of a generation of secondary messengers.
The effect of the signaling pathway is to activate or inhibit pumps, enzymes and gene transcription factors, all of which produce physiological changes.
Termination of the signal is crucial after the response is completed. The signaling process must be terminated or the cell loses responsiveness to new and important signals. One such signal is the signal to self-destruct, which prevents undesirable effects such as uncontrollable cell division and growth.

Cancers Caused by Viruses

Cancer is characterized by inappropriate cell growth, which is associated with defects in signaling pathway of proteins.

The study of cancers caused by viruses has greatly helped the understanding of signal transduction proteins and pathways.

An example of a virus that causes a type of cancer is Rous Sarcoma Virus. The Rous Sarcoma Virus is a retrovirus that causes sarcoma, a cancer of tissues of mesodermal origin such as muscle or connective tissue. The sarcoma virus carries a gene referred to as v-Src and is an oncogene which means that the gene causes a generation of cancer-like characteristics in cell types.

The v-Src gene is similar to a proto-oncogene referred to as the c-Src gene that encodes for a signal transduction that regulates cell growth. The difference between the v-Src gene and the c-Src gene that causes cancer is the substitution of a completely different set of 11 amino acids that lack the key tyrosine residue that is phosphorylated to inactivate the c-Src cell growth signal. Therefore, v-Src is always active. Small differences in the amino acid sequences between the proteins encoded are responsible for the product "oncogene" being swetched into the "on" position. The encoding proteins that are responsible are called protooncogene and oncogene.

Overexpression of Receptors

Tumors are usually caused by commonly mutated genes. An example is the gene encoding for Ras protein which is mutated so that it loses the ability to hydrolyze GTP, keeping the Ras protein to stimulate continuous cell growth.

Overexpressed receptors also lead to tumors. For example EGFR, epidermal growth factor receptor, in human epithelial cancers such as breast and ovarian cancer. The overexpression of the receptor increases the likelihood that a grow and divide signal is sent to the cell. In breast cancer, Her2 may be overexpressed and is breast cancer patients are now being offered testing for this EFGR family member that may stimulate cell proliferation during overexpression.

Apoptosis

Apoptosis occurs when a cell is damaged beyond repair, infected with a virus, or undergoing stressful conditions such as starvation. Damage to DNA from ionizing radiation or toxic chemicals can also induce apoptosis via the actions of the tumor-suppressing gene p53. The "decision" for apoptosis can come from the cell itself, from the surrounding tissue, or from a cell that is part of the immune system. In these cases apoptosis functions to remove the damaged cell, preventing it from sapping further nutrients from the organism, or halting further spread of viral infection. In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in an extensive variety of diseases. Excessive apoptosis causes hypotrophy, such as in ischemic damage, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer.Scientists believe that too much apoptosis is at least partly to blame for some neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s. On the other hand, unchecked mitosis can lead to cancer. In treating some cancers radiation and chemicals are used to induce apoptosis to stop the continual growth of cancerous cells. Apoptosis is nevertheless necessary for proper healthy development and needed to destroy cells that threaten the organism. Apoptosis works as a balance to mitosis to keep us healthy for example,our skin and hair cells are renewed via a continuous cycle of apoptosis and mitosis.

In apoptosis the cell shrinks and pulls away from its neighbor. Apoptosis causes the cells develop bubble like beads on their surface. The DNA in the nucleus condenses and breaks into regular sized fragments, and soon the nucleus itself, followed by the entire cell, disintegrates. The chromatin in the cell begins to degrade and mitochondria break down with the release of cytochrome c.

Some viruses associated with cancers use tricks to prevent apoptosis of the that they have transformed. Several human papilloma viruses(HPV) have been implicated in causing cervical cancer. One of them produces a E6 protein that binds and inactivates the apoptosis promoter p53. Mutations in the p53 gene are often found in cancer cells where apoptosis is not promoted to begin. Some viruses such as a type causing common colds make proteins mimic the off switch of cellular apoptosis fooling cells. Other viruses such as HIV have an enzyme that can disable a key component of the pathway, bringing the death march to a screeching halt.

A. normal cell division B. cancerous cell division 1. damaged cell 2. apoptosis

Apoptosis Inducing Factor: Apoptosis Inducing Factor (AIF) is a protein that triggers chromatin condensation and DNA degradation in a cell in order to induce programmed cell death. The mitochondrial AIF protein was found to be a capasase-independent death effector that can allow independent nuclei to undergo apoptotic changes. The process triggering apoptosis starts when the mitochondria releases AIF, which exits through the mitochondrial membrane, enters the cytosol, and finally ends up in the cell nucleus where it signals the cell to condense its chromosomes and fragment its DNA molecules in order to prepare for cell death. Recently, researchers have discovered that AIF is in fact dependent upon the type of cell, the apoptotic insult, and its DNA binding ability. AIF also plays a significant role in the mitochondrial respiratory chain as well as in metabolic redox reactions.

Synthesis of AIF:

The AIF protein is located across 16 exons on the X chromosome in humans. AIF1 (the most abundant type of AIF) is translated in the cytosol and is sent in the direction of the mitochondrial membrane and the intermembrane space by the C-terminus of an MLS protein. AIF is transported with the assistance of its bipartite N-terminal MLS protein into the inner and outer mitochondrial membrane enzymes to allow it to enter the organelle. Inside the mitochondria, AIF folds into its functional configuration by the help of the co-factor, flavin adenine dinucleotide (FAD). A protein called Scythe, which is used to regulate organogenesis, can increase the AIF lifetime in the cell. As a result, decreased amounts of Scythe lead to a quicker fragmentation of AIF. The x-linked inhibitor of apoptosis (XIAP) has the power to influence the half-life of AIF along with Scythe. Together, the two do not affect the AIF attached to the inner mitochondrial membrane, however they influence the stability of AIF once it exits the mitochondria.

Role of AIF in Mitochondria:

Researchers believed that if a recombinant version of AIF lacks the first 120 amino acids of the AIF protein, then AIF would function as an NADH and NADPH oxidase. They discovered however, that recombinant AIF that do not have the last 100 N-terminal amino acids have limited NADP and NADPH oxidase activity. Therefore, researchers concluded that the AIF N-terminus may function in interactions with other proteins or control AIF redox reactions and substrate specificity.

AIF Respiratory Chain Complex I:

Mutations of AIF due to deletions have stimulated the creation of the mouse model of complex I deficiency. Complex I deficiency is the reason behind over thirty percent of human mitochondrial diseases. For example, complex I mitochondriopathies mostly affect infants by causing symptoms such as seizures, blindness, deafness, etc. These AIF-deficient mouse models are important for fixing complex I deficiencies. The identification of AIF-interacting proteins in the inner mitochondrial membrane and intermembrane space will help researchers identify the mechanism of the signaling pathway that monitors the function of AIF in the mitochondria.

Necrosis

Unlike apoptosis necrosis is the premature death of cells and living tissue. Necrosis is often caused by external factors, such as infection, toxins or trauma. During necrosis, the cell’s outer membrane loses its ability to control the flow of liquid into and out of the cell. Necrosis is a form of traumatic cell death that results from acute cellular injury. Apoptosis in contrast to necrosis, confers advantages during an organism's life cycle. For instance during the development of the fetus in the mother, the differentiation of fingers and toes occurs because cells between the fingers apoptose with the end result that the digits are separate. Approximately between 50 billion and 70 billion cells die each day due to apoptosis in the average human adult. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight. Apoptosis differentiates from necrosis as the processes associated with apoptosis in disposal of cellular debris do not damage the organism in apoptosis.

References

http://learn.genetics.utah.edu/content/begin/cells/badcom/ http://www.wentek.com/jean/research.htm Biochemistry, Sixth Edition. Authors: Jeremy M. Berg, John L Tymoczko, Lubert Stryer http://apoptosisinfo.com/ Inside the Cell. US Department of Health and Human Resources and the National Institute of General Medical Sciences.

Trends Biochem Sci. 2010 May;35(5):278-87. Epub 2010 Feb 6. Life with or without AIF. Hangen E, Blomgren K, B√©nit P, Kroemer G, Modjtahedi N. INSERM U848, 94805 Villejuif Cedex, France.