Monday, July 27, 2009

Mutations : Germline mutations and somatic mutations

Mutations defined as changes in the sequence of the bases, can occur by a number of means: for example, single base substitutions that might result from errors during DNA replication (copying of the DNA prior to cell division; see below), or deletion of larger pieces of a chromosome or translocation events (swapping pieces from one chromosome to another).

It is also important to note that mutations can be grouped into two general categories, germline and somatic.

Germline mutations are those that we inherit from our parents and will pass on to our children, while somatic mutations are those that occur during our lifetime and are not passed on to our descendants. Most mutations have no effect on our health and lifespan because they result in changes to DNA base sequences that do not alter the coded genetic information.

However, those mutations that make changes to the genetic information such that cells no longer can control their growth are the hallmark of cancer. The discovery of the structure of DNA in 1953 by James Watson and Francis Crick initiated a rapid increase in the study of how the information encoded in the double-helical fibers of DNA was copied and passed from generation to generation. It has been estimated that the human genome carries approximately 35,000 sequences whose codes are read to produce protein molecules with specific metabolic functions.

In cells that are growing and dividing, and even in those cells in a resting phase, mutations occur at an alarmingly high rate, both from normal cellular processes (e.g., copying of the DNA strands prior to cell division) and from exposure to environmental or chemical carcinogens [e.g., the ultraviolet rays in sunlight or especially cigarette smoke (at least 40 different carcinogens are found in a typical cigarette)]. However, all cells use remarkably effective strategies to either avoid mutations or to repair them when they occur.

The Base pairs in a DNA Strand - A : Tand G : C

The bases in each of the two DNA strands form what arereferred to as base pairs, and each strand is polymerized in an orientation oppositerelative to its partner. The chemical composition of the bases dictates that A always pairs with T on the opposite strand, and G with C. Hence, normal DNA contains only A : Tand G : C base pairs.

Mutations defined as changes in the sequence of the bases, can occur by a number of means: for example, single base substitutions that might result from errors during DNA replication (copying of the DNA prior to cell division; see below), or deletion of larger pieces of a chromosome or translocation events (swapping pieces from one chromosome to another).

MUTATIONS AND CELL DEFENSES

INTRODUCTION
The information required for the development and growth of an organism is encoded in its deoxyribonucleic acid (DNA), the genetic material. In human cells, the entire DNA content, or genome, is packaged in 46 chromosomes that reside in the cell’s nucleus. Because this information is critically important for all biological processes occurring during the lifetime of an organism, evolution has resulted in many and various means by which a cell can either avoid damage to this information, or repair damage once it has occurred.

DNA is a double-strandedhelical ribbon, with each strand consisting of a continuous sequence of bases. Bases can be considered as the letters of words that are strung together to make up the information code. Remarkably, only four bases—adenine, guanine, cytosine, and thymine (A, G, C, and T)—are required to generate the amazingly diverse information encoded in the human genome, and it is the varying, ordered sequence of these bases that creates all the different bits of information along the DNA strand. For the purposes of our discussion in this chapter, remember that genetic information is decoded by the following general path: DNA codes for ribonucleic (RNA), acid which in turn codes for protein molecules, whose amino acid sequence derives from the DNA sequence. Although this is an oversimplification of the complex information contained within DNA, it suffices for our appreciation of how changes in the DNA sequence (mutations) may adversely effect cellular function.

Sunday, July 26, 2009

Cell signaling

Cells communicate and respond to the extracellular environment through a process designated signal transduction. Signal molecules bind to transmembrane receptors that span the cell membrane. The interaction of signal molecules with components of receptors located outside the cell modifies the intracellular components of the receptors. An environmental signal is thereby transduced into a cascade of regulatory steps that control genes which control cell proliferation and specialized properties of cells.

In some signaling pathways, scaffold proteins assemble signaling molecules into complexes for the initial passage of information from the transmembrane receptor to relay and adaptor proteins. Subsequent steps in the signaling process amplify and integrate signals. A chain of intracellular signaling proteins processes regulatory information through the cytoplasm and into the cell nucleus to activate or suppress genes. In other signaling pathways the regulatory cascades are abbreviated. The transduction of regulatory information from the intracellular component of the transmembrane receptor is more direct, circumventing intermediary steps in information transfer. At an early stage in the signaling process a signaling protein enters the nucleus and interacts directly with genes to modify expression.

Many cancer cells exhibit defects in one or more steps of signaling cascades that alter control of
cell growth, specialized cell properties, cell–cell communication, cell motility, and cell adhesion. The components of signaling pathways that are modified in tumor cells are targets for treatments that are effective and specific.

Stem cells and Cancer cells

Stem cells are multipotential in nature. They can develop into any type of tissue (differentiate) and thereby create various tissues and eventually ‘‘build’’ organs such as muscle, liver, or blood. The differentiated cells function in specialized ways, and most of them stop growing. Stem cells fail to stop dividing. Tumors contain immature cells that exhibit differentiation failures. Such a rare defectively differentiated subset of stem cells in tissues has been proposed as the origin of tumor cells. An example is acute promyelocytic leukemia, where stem cells have been blocked from achieving differentiation.

Normal cells can stop growing permanently, a process of arrest that is designated cell senescence. Cells survive for varying lengths of times. At one extreme, brain cellsmight last a lifetime, butwhite cells in blood survive for only about twomonths. Cancer cells, in contrast, are immortalized and have an unlimited potential to proliferate. This indefinite proliferation requires activity of telomerase, an enzyme that at each cycle of the cell adds back DNA sequences of telomeres to the ends of chromosomes. Telomerase is active inmalignant cancer cells but not in normal cells

General and tumor-type specific modifications

General and tumor-type specific modifications in nuclear organization are long-standing indications of cancer. Many cancers have alterations in the number and composition of nucleoli , the focal sites within the cell nucleus for ribosomal gene expression that supports protein synthesis. Chromosomal rearrangements are prevalent in cancer. Modifications in plasma membrane–associated receptors modify responses of the tumor cell to growth factors. Changes in integrins, molecules that mediate communication between the extracellular environment and the cytoplasm within a cancer cell, influence the transmission of information .

Cancer-related alterations occur in the exchange of signals between the cell nucleus and cytoplasm, which are critical for control of cell regulatory machinery. These changes provide insight into cellular and molecular parameters of cancer that facilitate tumor diagnosis and are targets for therapy. Effects of mutation that are found in most cancer cells are failures of molecular mechanisms that limit growth and differentiation into specialized cells, causing their death (apoptosis), their movement out of the tumor (metastasis), and the activation of a blood supply, which is required to feed the tumor (angiogenesis).

CANCER CELL BIOLOGY

Cells are the units of life. Normal cells act on each other to control their growth and other properties in balance with the entire organism. They are closely regulated by a variety of genetic and biochemical processes. For example, biological feedbacks act in much the same way that a thermostat controls heat production by a furnace. Cancer is a disease of ‘‘outlaw’’ cells, cells that have lost their normal relationship to the whole organism. A tumor originates when single normal cells mutate and develop into cancer cells, termed transformed cells. Mutations produce defects in their cellular regulatory mechanisms, changing their biochemistry and biology so that they differ from normal cells in structure and functioning and grow at the wrong times and in the wrong places.

Briefly, each cell is surrounded by a membrane that separates it from its surroundings, which include other cells, nutrients, and molecules that regulate growth and other functions. Within the cell is a fluid, cytoplasm, containing proteins and structures, including mitochondria (the source of energy for a cell , that produce chemical energy and the machinery (ribosomes) that synthesizes proteins. The nucleus, which contains the genetic material, sits in the middle of the cell. Location within a cell can determine a molecule’s possible biochemical interactions and effects. Cells of cancers develop into disorganized arrangements, and their nuclear shapes are abnormal, properties that are scrutinized carefully during diagnosis and are used to classify the stage of a cancer.

Cancer-related chromosomal aberrations

Visible changes in the structure of chromosomes in cancer cells provide direct evidence for the genetic basis of cancer. Rearrangements at many definite positions have been observed repeatedly in many types of cancers . At the molecular level are found miscoding changes, including substitutions, deletions, duplications, and rearrangements of DNA building blocks. For example, in a recent study of breast and colon cancers, 189 genes (average 11 per tumor) were frequently found to be mutated. In several cancers, mutations change the functioning of genes located at their positions. DNA is often altered in human chromosome 6 at position p21, where the cancer-related K-ras oncogene, a gene that may modify cell growth aberrantly and lead to cancer, is located. Additional copies of a particular gene make a cell resistant to the anticancer drug methotrexate. Rare cancers are produced by virus infection; for example, introduction of genetic material by the human papilloma virus causes cervical cancers. This provides further evidence for the genetic basis of cancer.

GENES, MUTATIONS, AND CANCER

These connections with environmental factors suggest that some cancers could originate from agents that change a cell’s genetic material (mutation). Each of the more than 100 trillion cells in a human body carries its genetic information in deoxyribonucleic acid (DNA), composed of long double-helical strands made of sequences of four building blocks (bases) linked in pairs. It is packaged in 23 pairs of chromosomes which can be seen with a microscope. The DNA in each cell carries information equal to the letters in 600 encyclopedia volumes. Genes are sequences of DNA that code for individual proteins.

Mutations are errors in DNA structure that alter this genetic information. Most mutations arise spontaneously, possibly from mistakes that arise while DNA duplicates during cell growth. Experiments have shown that foods contain many chemicals that cause carcinogenic damage to DNA. Errors can also be produced by damage from toxic chemicals (carcinogens) or radiation. Cell growth is stopped when molecular mechanisms termed checkpoints sense the damage, recruit the molecules to rectify the problem, and give time for corrections to be made.

Then enzymes for repair are activated, and the cell may recover if the damage was not too severe. Genes designated BRCA1 and BRCA2 are involved in DNA repair and are mutated in some breast and ovarian cancers. The inability to repair damaged DNA may result in cancer.
Structure and organization of regulatory machinery in cancer cells.
The organization and location of machinery that controls genes is modified during the
onset and progression of cancer.


THE DISEASE

About a third of humans develop cancer in a lifetime. Cancer starts as an abnormal cell which grows with time into a mass of cells, some of which can spread to other. locations in the body (metastasize), where they grow and upset normal bodily functions. It is one of the most frequent causes of human death. The rate of death varies greatly for different types of cancer. Lung and pancreatic cancer are the worst, usually fatal within a year. But not all cancers are fatal: Only one-fifth of breast cases result in death. Successful treatments utilize surgery, radiation, drugs,
and immunology.