CELL BIOLOGY 3 APOPTOSIS CELL CYCLE APOPTOSIS Definition

CELL BIOLOGY (3) APOPTOSIS & CELL CYCLE

APOPTOSIS

Definition Apoptosis or programmed cell death, is coordinated collapse of cell, protein degradation , DNA fragmentation followed by rapid engulfment by neighboring cells. Apoptosis is gene directed active form of cell death Between 50 and 70 billion cells die each day due to apoptosis in the average human adult.

Why should a cell commit suicide? 1. Apoptosis is needed for proper development Examples: The formation of the fingers and toes of the fetus and the formation of the proper connections between neurons in the brain 2. Apoptosis is needed to destroy cells as defense mechanism Examples: Cells infected with viruses or with DNA damage or cancer cells 3. In aging , senescence and tissue degeneration

APOPTOSIS vs NECROSIS In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis is a highly regulated and controlled process that confers advantages during an organism's lifecycle.

Necrosis vs. Apoptosis Necrosis • • • Passive death External stimulus Cellular swelling Membranes are broken ATP is depleted Cell lyses, eliciting an inflammatory reaction • DNA fragmentation is random, or smeared • In vivo, whole areas of the tissue are affected Apoptosis • • • Active death Internal or external stimulus Cellular condensation (shrink) Membranes remain intact Requires ATP Cell is phagocytosed, no tissue reaction • Ladder-like DNA fragmentation • In vivo, individual cells appear affected

NECROSIS Vs APOPTOSIS Wilde, 1999

Molecular mechanism of apoptosis q Because apoptosis cannot stop once it has begun, it is a highly regulated process. q Apoptosis can be initiated through one of two pathways. q In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. q Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins. q The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by degrading proteins indiscriminately.

A. Extrinsic pathway - Initiated by death receptors (FAS or TNF receptors) , start with ligand binding to death receptors and then activate pro caspase 8 to yield caspase 8 (active) that triggers effector caspases, (caspase 3, 7). - Activation of death receptors may also activate intrinsic pathway. - TNF or Fas. L are expressed by activated T immune cells to begin death programme to other cells.

B. Intrinsic Pathway - Usually initiated by cellular stress (UV, cytotoxic drugs, reactive oxygen species) as all leads to change in mitochondrial membrane permeability (MMP) - Regulated by Bcl-2 family member of proteins – regulate the release of pro-apoptotic factors from mitochondria. Pro apoptotic : e. g. Bax , Bad Anti apoptotic : e. g. Bcl-2 - Battle between the ratio of pro and anti levels to determine cell’s response to apoptotic stimuli such as ROS (reactive oxygen species), radiation etc.

Apoptosis: Pathways “Extrinsic Pathway” Death Ligands Death Receptors “Intrinsic Pathway” DNA damage & p 53 Mitochondria/ Cytochrome C Initiator Caspase 8 Effector Caspase 3 Initiator Caspase 9 APOPTPSIS

APOPTOSIS: Role in Disease TOO MUCH: Tissue atrophy Neurodegeneration AIDs (lymphocyte induced depletion) TOO LITTLE: Hyperplasia Cancer Autoimmune diseases (reactive lymphocytes not removed)

APOPTOSIS: Role in Disease Neurodegeneration Neurons are post-mitotic (cannot replace themselves) Neuronal dysfunction or damage results in loss of synapses and neurons that leads to : PARKINSON'S DISEASE ALZHEIMER'S DISEASE

APOPTOSIS: Role in Disease Cancer Apoptosis eliminates damaged cells (damage => mutations => cancer Tumor suppressor p 53 controls apoptosis responses to damage Most cancer cells are defective in apoptotic response (damaged, mutant cells (P 53 mutant) survive) High levels of anti-apoptotic proteins or Low levels of pro-apoptotic proteins ===> CANCER

CELL CYCLE

CELL CYCLE… � All multicellular organisms use cell division for growth and the maintenance and repair of cells and tissues. � Single-celled organisms use cell division as their method of reproduction. � Somatic cells divide regularly; all human cells (except for the cells that produce eggs and sperm) are somatic cells. � Somatic cells contain two copies of each of their chromosomes (one copy from each parent). � The cell cycle has two major phases: interphase and the mitotic phase. � During interphase, the cell grows and DNA is replicated; during the mitotic phase, the replicated DNA and cytoplasmic contents are separated and the cell divides.

Key Terms �somatic cell: any normal body cell of an organism that is not involved in reproduction; a cell that is not on the germline �interphase: the stage in the life cycle of a cell where the cell grows and DNA is replicated �mitotic phase: replicated DNA and the cytoplasmic material are divided into two identical cells

G 1 Phase (First Gap) �The first stage of interphase is called the G 1 phase (first gap) because, from a microscopic aspect, little change is visible. �However, during the G 1 stage, the cell is quite active at the biochemical level. The cell grows and accumulates the building blocks of chromosomal DNA and the associated proteins as well as sufficient energy reserves to complete the task of replicating each chromosome in the

S Phase (Synthesis of DNA) �The synthesis phase of interphase takes the longest because of the complexity of the genetic material being duplicated. Throughout interphase, nuclear DNA remains in a semi-condensed chromatin configuration. �In the S phase, DNA replication results in the formation of identical pairs of DNA molecules, sister chromatids, that are firmly attached to the centromeric region.

G 2 Phase (Second Gap) �In the G 2 phase, the cell replenishes its energy stores and synthesizes proteins necessary for chromosome manipulation. There may be additional cell growth during G 2. The final preparations for the mitotic phase must be completed before the cell is able to enter the first stage of mitosis. The Mitotic Phase and the G 0 Phase �During the multistep mitotic phase, the cell nucleus divides, and the cell components split into two identical daughter cells.

CANCER & CELL CYCLE �Proto- oncogenes positively regulate the cell cycle. �Mutations may cause proto-oncogenes to become oncogenes, disrupting normal cell division and causing cancers to form. �Some mutations prevent the cell from reproducing, which keeps the mutations from being passed on. �If a mutated cell is able to reproduce because the cell division regulators are damaged, then the mutation will be passed on, possibly accumulating more mutations with successive divisions.

Key Terms �proto-oncogene: a gene that promotes the specialization and division of normal cells that becomes an oncogene following mutation �mutation: any heritable change of the base-pair sequence of genetic material �oncogene: any gene that contributes to the conversion of a normal cell into a cancerous cell when mutated or expressed at high levels

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USEFUL LINKS • https: //www. youtube. com/watch? v=7 WRk Y 8 q_F 3 k • https: //www. youtube. com/watch? v=Syv. OP Xeg 4 ig • http: //www. mcqlearn. com/biology/g 9/apopt osis-and-necrosis-mcqs. php