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Early Embryonic Development Maternal effect gene products set the stage by controlling the expression of the first embryonic genes. 1. Transcription factors 2. Receptors 3. Regulatory proteins Maternal effect gene products form a gradient of concentration across the embryo. Zygotic Genes Zygotic genes are the first genes expressed by the embryo in response to signals from the maternal effect genes. The first of these genes are broadly classed into two categories, segmentation genes and selector genes. Zygotic Genes Segmentation genes 1. 2. Divide the embryo into segments Define the number, size and polarity of each segment. Zygotic Genes Selector genes specify the identity or fate of each segment. Segment Formation Segmentation is controlled by three classes of genes: 1. Gap proteins 2. Pair-rule genes 3. Segment polarity genes These gene products act in a coordinated fashion to divide the embryo into segments, then create an orientation within the segments. Development Once the segments have been formed, selector genes are activated and specify the developmental fate of cells within the segment. Selector genes determine the structures that will ultimately form. Genetics and Cancer Normal cell function and cell lifespan is closely regulated by careful regulation of the timing of cell division. Cancer is, at its core, unregulated tissue growth: 1) Uncontrolled cell division 2) Metastasis, or spread, of cancer cells away from their original site to other locations in the body. Mutations and Cancer Mutations that influence the development and progression of cancer can be small or large: 1. Small changes, such as a single base mutation or frameshift mutation that results in an abnormal protein. 2. Large changes such as chromosomal losses, gains or rearrangements, or integration of viral genomes into chromosomes. Mutations and Cancer Mutations will always arise at some spontaneous rate because of inherent imperfections in the DNA replication process. Carcinogens are environmental substances that impair the replication process at some level such that mutations are introduced at a rate above baseline and promote the formation of cancer. Known Mutagens and Carcinogens Ionizing radiation Viruses Environmental chemicals Typically, more than one mutational event must occur. Cancer Susceptibility Genes Cancer is known to run in families, though usually there is no clear-cut pattern of inheritance. Individuals may inherit a mutant alelle that predisposes them to cancer (increases risk of developing cancer) by influencing the age of onset and severity of cancer. Cell Cycle The phases of the cell cycle are the G1, S, G2 (interphase) and M phases. Some cell types continuously move through the cell cycle (skin, GI tract lining), dividing at regular intervals. Other cell types move through the cell cycle only intermittently. Some cell types withdraw from the cell cycle and enter a permanently non-dividing state called G0. Cell Cycle Progression from one phase to the next is tightly controlled. Cell-cycle checkpoints are the places in the cell cycle in which progression are regulated. The major checkpoints are at the transitions from 1) G1 to S 2) G2 to M 3) M (transition into anaphase) Cell-Cycle Regulation Any mutation that interferes with regulation of the cell cycle is a candidate carcinogen. De-regulation of the cell-cycle disrupts the ability of a cell to control its division and increases the probability of unrestricted cell growth. Control of Cell Division Control of cell division is both negative and positive. 1. Inhibition of cell division (tumor suppressor genes) 2. Promotion of cell division (protooncogenes) Tumor Suppressor Genes Under normal circumstances, tumor suppressor genes halt progression through the cell cycle. For cell division to occur, these gene products must be absent or inactivated. If tumor suppressor genes become permanently inactivated or deleted, control of cell division is lost and the cell enters uncontrolled proliferation. Usually, both alleles must be mutant for tumor suppressor activity to be lost.. (One normal copy is enough to suppress cell division) Recessive Major Tumor Suppressors Retinoblastoma gene (Rb): Controls the G1 to S transition. Although it is always expressed such that the protein is normally present, cells can make the G1/S transition only when Rb is inactivated by phosphorylation. Wilms tumor gene (WT): Encodes a transcription factor that controls cell division, although the precise function is unknown. Major Tumor Suppressor Genes p53: A transcription factor involved in cell cycle arrest, DNA repair and induction of apoptosis (programmed cell death). At least 20 genes are known to be regulated by p53, and as much as 50% of all cancers are thought to be associated with malfunctions in p53. BRCA1/BRCA2: Breast cancer susceptibility genes, thought to be involved in DNA repair mechanisms. Protooncogenes When these genes are activated, they promote cell division. For cell division to be “turned off,” these genes must be absent or inactivated. If protooncogenes are permanently “turned on,” the cells enter into uncontrolled proliferation. Major Protooncogenes Protooncogenes are the normal form of oncogenes. Oncogenes are the mutant alleles that cause cancer by promoting uncontrolled cell growth. Typically, only one mutant allele is sufficient to deregulate cell growth. (Dominant) Many oncogenes are identified with viruses. Major Oncogenes Src: A membrane protein originally identified as the transforming principle of Rous sarcoma virus (RSV) Ras: A signal transduction protein that transmits signals from the external cell environment and promotes cell division. Metastasis Metastasis is invasion of cancer cells into other parts of the body, where they divide and form secondary tumors. Metastasis is often what ultimately causes death from cancer. Cancer cells escape the primary tissue by entering the blood or lymphatic system. Metastasis Tumor cells with high metastatic capacity produce large amounts of enzymes called metalloproteinases, which digest the extracellular framework and allow the tumor cells to penetrate and migrate. Normal cells inhibit migration by producing TIMP, or Tissue Inhibitor of Metalloproteinases. Metastasis occurs when there is not enough TIMP to suppress metalloproteinase activity.