Chapter 12 Note - The Cell Cycle
Chapter 12 Note - The Cell Cycle BIOL 2311
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This 14 page Class Notes was uploaded by Ming-Han Lu on Tuesday July 12, 2016. The Class Notes belongs to BIOL 2311 at University of Texas at Dallas taught by Dr. Mehmet Candas in Summer 2016. Since its upload, it has received 41 views. For similar materials see Biology 2311 in Biology at University of Texas at Dallas.
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Date Created: 07/12/16
Chapter 12 – The Cell Cycle MingHan Lu Cell division – new cells arise by splitting preexisting cells (hypothesis by Rudolf Virchow) studies of embryos (newly developing organisms) confirmed Virchow’s hypothesis 2 different ways that nuclei divide before cell division: meiosis and mitosis. Meiosis leads to the production of sperm and eggs, which are the male and female reproductive cells termed gametes. Mitosis leads to the production of all other cell types, referred to as somatic cells. both of these processes are accompanied by cytokinesis – division of cytoplasm into two distinct cells. when cytokinesis is done, parent cell give rise to 2 daughter cells mitotic + meiotic are responsible for reproduction difference: mitosis, replication results in the daughter cells being genetically identical with original parent cell. Meiosis results in daughter cells that are genetically diff from each other & have half the amount of hereditary material as the parent cell. 12.1 How Do Cells Replicate? General requirements for cell replication are (1) copy the DNA, (2) separate the copies, and (3) divide the cytoplasm to create complete cells. 3 Key Events because of eukaryotic cell replication: 1. Growth 2. Wound repair 3. Asexual Regeneration – produces offspring that are genetically identical with the parent. What is a Chromosome? A chromosome consists of a single, long DNA double helix that is wrapped around proteins, called histones, in a highly organized manner. DNA encodes the cell’s hereditary information, or genetic material. A gene is a length of DNA that codes for a particular protein or ribonucleic acid (RNA) found in the cell. Each of the DNA copies in a replicated chromosome is called a chromatid. Before mitosis, the two chromatids are joined along their entire lengths by proteins called cohesins. Once mitosis begins, these connections are removed except for the specialized region of the chromosome called the centromere. Chromatid copies that remain attached at their centromere are called sister chromatids. Chapter 12 – The Cell Cycle MingHan Lu Cells Alternate between M Phase and Interphase Dividing phase = M (mitotic or meiotic) phase The rest of the time, the cell is in interphase (it’s still an active time though: The cell is either growing and preparing to divide or fulfilling its specialized function in a multicellular individual; Cells spend most time in interphase). The Discovery of S Phase used autoradiography (use of radioactive isotope to label DNA) proved that DNA replication occurs during interphase. called it synthesis (or S) phase. S phase is part of interphase. Replication of the genetic material is separated, in time, from the partitioning of chromosome copies during M phase. cell cycle – orderly sequence of events that leads a eukaryotic cell through the duplication of its chromosomes to the time it divides. The Discovery of the Gap Phases There was at least one “gap” in interphase when DNA was not being copied. Using pulsechase approach & asynchronous cultures they found out that there are two gaps: the gap between the end of M and start of S phase is called the G 1 phase. The second gap, between the end of S and start of M phase, is called the G 2phase. Asynchronous cultures are helpful because at every tick, there would be at least one cell present. As time passes, these cells would move around this cell cycle at the same rate and in the same direction. The Cell Cycle The cell cycle consists of 4 phases: M phase and an interphase consisting of the G 1 S, and G 2hases. The timing of phases varies depending on the the cell type & growth condition. Gap phases exist because cells also must prepare for division by replicating organelles and increasing in size. Before mitosis can take place, the parent cell must grow large enough to divide into two cells that will be normal in size and function. The two gap phases provide the time required to accomplish these tasks. 12.2 What Happens during M Phase? M phases consists of two events: the division of the nucleus and the division of the cytoplasm. During cell replication, mitosis divides the replicated chromosomes to form two daughter nuclei with identical chromosomes and genes. Mitosis is usually accompanied by cytokinesis – cytoplasmic division that results in two daughter cells. Chapter 12 – The Cell Cycle MingHan Lu Eukaryotic chromosomes consist of DNA wrapped around the globular histone proteins. In eukaryotes, this DNAprotein material is called chromatin. o During interphase, the chromatin of each chromosome is in a “relaxed” or uncondensed state, forming long, thing strands. o Each chromatid contains one long DNA double helix, and sister chromatids represent exact copies of the same genetic information. At the start of mitosis, each chromosome consists of two sister chromatids that are attached to each other at the centromere. Events in Mitosis Mitosis begins when chromatin condenses to form a much more compact structure. During mitosis, the two sister chromatids separate to form independent daughter chromosomes. One copy of each chromosome goes to teach of the two daughter cells. o As a result, each cell receives an identical copy of the genetic information that was contained in the parent cell. 5 mitotic subphases within M phase 1. prophase 2. prometaphase 3. metaphase 4. anaphase 5. telophase Prophase Mitosis begins with the events of prophase, when chromosomes condense into compact structures. Chromosomes first become visible in the light microscope during prophase. o Chromosomes first become visible in the light microscope during prophase. o Prophase is marked by the formation of the spindle apparatus (SA) SA is a structure that produces mechanical forces that 1. Move replicated chromosomes during early mitosis 2. Pull chromatids apart in late mitosis The spindle consists of microtubules (originating from the microtubuleorganizing centers [MTOCs]) – components of the cytoskeleton. The MTOCs define the two poles of the spindle and produce large numbers of microtubules. The MTOC is a centrosome —a structure that contains a pair of centrioles. o During prophase, some of these microtubules extend from each spindle pole and overlap with one another – theses are called polar microtubules. Chapter 12 – The Cell Cycle MingHan Lu During prophase in animal cells, the spindle begins to form around the chromosomes by moving centrosomes to opposite sides of the nucleus. Prometaphase Once chromosomes have condensed, the nuclear envelope disintegrates. Once the envelope has been removed, microtubules are able to attach to chromosomes at specialized structures called kinetochores. o These events happen at the prometaphase (“before middlephase”) o Each sister chromatid has its own kinetochore, which is assembled at the centromere. Since the centromere is also the attachment site for chromatids, the result is two kinetochores on opposite sides of each replicated chromosome. The microtubules that are attached to these structures are called kinetochore microtubules. Kinesis and dynein motors are recruited at the kinetochore, where they can “walk” the chromosome up and down microtubules. o Similar to the transportation of vesicles on microtubules. o After the kinetochores have attached to microtubules, chromosomes begin to move to the middle of the cell during prometaphase. Chapter 12 – The Cell Cycle MingHan Lu Metaphase once the kinetochore microtubules moved all the chromosomes to the middle of the spindle, the mitotic cells enter metaphase (“middlephase”). o At this point chromosomes are lined up along an imaginary plane between the 2 spindle poles called the metaphase plate. o Each chromosome is held by kinetochore microtubules reaching out from opposite poles and exerting the same amt of tension, or pull. o The spindle poles are held in place partly because of the astral microtubules that extend from the MTOCs and interact with the proteins on the cell membrane. Alignment of these chromosomes results from the growth and shrinkage of the attached kinetochore microtubules. When chromosomes reach the metaphase plate, the shrinkage of these microtubules at the MTOCs is balanced by slow growth of microtubules at the kinetochores. Since the sister chromatids of each chromosome are connected to opposite poles, a tug of war occurs during metaphase that pulls them in opposite directions. Anaphase Cohesions that are holding sister chromatids together at the centromeres split. Because the chromatids are under tension, each replicated chromosome is pulled apart to create two independent daughter chromosomes. o This separation of chromatids instantly doubles the number of chromosomes in the cell. Two types of movement occur during anaphase: 1. Daughter chromosomes move to opposite poles via the attachment of kinetochore proteins to the shrinking kinetochore microtubules. 2. The two poles of the spindle are pushed and pulled farther apart. The motor proteins in overlapping polar microtubules push the poles away from each other. Different motors on the membrane walk along on the astral microtubules to pull the poles to opposite sides of the cell. When anaphase is complete, two complete collections of chromosomes are fully separated, each being identical with those of the parent cell before chromosome replication. Telophase The nuclear envelope that dissolved in prometaphase reforms around each set of chromosomes, and the chromosomes begin to decondense. (Note: think of it as a phoenix rising from the ashes but two rise this time) Once two independent nuclei have formed, mitosis is complete. At this point, most cells will go on to divide their cytoplasm via cytokinesis to form two daughter cells. Chapter 12 – The Cell Cycle MingHan Lu How do Chromosomes Move During Anaphase? The exact and equal partitioning of genetic material to the two daughter nuclei is the most fundamental aspect of mitosis. Mitotic Spindle Forces The spindle apparatus is composed of microtubules. Recall that: 1. Microtubules are composed of tubulin and tubulin dimers, 2. Microtubules are asymmetric – meaning they have a plus end and a minus end, and 3. The plus end is the site where microtubule growth normally occurs while disassembly is more frequent at the minus end. During mitosis, the microtubules originating from the poles are highly dynamic. Rapid growth and a shrinkage ensures that some of the microtubules will be able to attach to kinetochores with their plus ends. Others will be stabilized by different proteins in the cytoplasm and become polar/astral microtubules. Chapter 12 – The Cell Cycle MingHan Lu o Results suggest that the kinetochore microtubules remain stationary during anaphase, but shorten because tubulin subunits are lost from their plus ends. As microtubule ends shrink back to the spindle poles, the chromosomes are pulled along. Kinetochores Are Linked to Retreating Microtubule Ends The kinetochore is a complex of many proteins that build a base on the centromere region of the chromosome and a “crown” of fibrous proteins projecting outward. As anaphase gets under way, the plus ends of the kinetochore microtubules begin to fray and disassemble. Fibers that extend from the yeast kinetochore are tied to this retreating end by attaching to a ring that surrounds the kinetochore microtubule. As the fraying ends widens, its expansion forces the ring, and the attached chromosome, toward the minus end of the microtubule. o Result: the chromosome is pulled to the spindle pole by the depolymerization of the kinetochore microtubule. Cytokinesis Results in Two Daughter Cells While the cell is in interphase, the cytoplasmic contents, including the organelles, have increased in number of volume. o During cytokinesis, the cytoplasm divides to form two daughter cells, each with its own nucleus and complete set of organelles. Cytokinesis follows mitosis In plants, polar microtubules left over from the spindle help define and organize the region where the new plasma membranes and cell walls will form. o Vesicles from the Golgi apparatus carry components to build a new cell wall to the middle the dividing cell. These vesicles are moved along the polar microtubules via motor proteins. In the middle of what was the spindle, the vesicles start to fuse together to form a flattened saclike structure called the cell plate. The cell plate continues to grow as new vesicles fuse with it, eventually contacting the existing plasma membrane. When the cell plate fuses with the existing plasma membrane, it divides the cell into two new daughter cells. In animals and other cell eukaryotes, cytokinesis begins with the formation of a cleavage furrow. o The furrow appears because of a ring of actin filaments forms just inside the plasma membrane, in the middle of what used to be the spindle. Myosin motor proteins bind to these actin filaments and use ATP to contract in a way that causes actin filaments to slide. Chapter 12 – The Cell Cycle MingHan Lu As myosin moves the ring of actin filaments, the ring shrinks in size and tightens. It pulls the plasma membrane with it. Continues until the formation of two cells is complete. Mechanisms involved in accomplishing chromosome separation and cytoplasmic division vary depending on the type of cell. o Prokaryotes vs. Eukaryotes Chapter 12 – The Cell Cycle MingHan Lu Bacterial Cell Replication Bacteria divide using binary fission. o Similar to the eukaryotic M phase. o Protein filaments attach to the copies and separate them to opposite sides of the cell. o Rest is pretty self explanatory! Signal filament ring constricts two identical cells. 12.3 Control of the Cell Cycle Cells divide at different speeds. o Differences are due to variation in the length of the G ph1se. In rapidly dividing cells, G1 is essentially eliminating; whereas, most nondividing cells, are permanently stuck in G .1Researchers refer to this arrested stage as the G 0tate, or simply “G zero.” Cells that are in the G 0ave effectively exited the cell cycle (sometimes referred to as the postmitotic). Nerve cells, muscle cells, and many other cell types enters enter G 0 once they have matured. A cell’s division rate can also vary in response to changing conditions. The Discovery of CellCycle Regulatory Molecules The factor that initiates Mphase in oocytes was purified and is now called M phasepromoting factor, or MPF (it is EVERYWHERE the cytoplasm of M phase cells. If you induce a interphase cell with the cytoplasm of Mphase cells, the interphase cell will start mitosis). o Subsequent experiments showed that MPF induces M phase in all eukaryotes. MPF = “Start M phase” signal MPF Contains a Protein Kinase and a Cyclin MPF is made up of two distinct polypeptide subunits. One subunit is a protein kinase—an enzyme that catalyzes the transfer of a phosphate group from ATP to a target protein. o The phosphorylation may activate or inactivate the function of proteins by changing their shape. Kinases act as regulatory proteins in the cell. Chapter 12 – The Cell Cycle MingHan Lu Cyclins (a family of proteins also the second MPF subunit) – they got their name because their concentrations fluctuate throughout the cell cycle. o The concentration of the cyclin associated with MPF builds during interphase and peaks in M phase. The timing of this increase is important because the protein kinase subunit in MPF is functional only when it is bound to the cyclin subunit. As a result, the protein kinase subunit of MPF is called a cyclindependent kinase, or Cdk. MPF is a dimer consisting of a cyclin and a cyclindependent kinase. The cyclin subunit regulates the formation of the MPF dimer; the kinase subunit catalyzes the phosphorylation of other proteins to start M phase. How is MPF Turned On? Why doesn’t the increasing concentration of MPF trigger the onset of M phase? The answer is that the activity of MPF’s Cdk subunit is further regulated by two phosphorylation events. The phosphorylation of one site in Cdk activates the kinase, but when the second site is phosphorylated, it is inactivated. o Both these sites are phosphorylated after cyclin binds to the Cdk. This allows the concentration of the dimer to increase without prematurely starting M phase. Later in G2, an enzyme removes the inhibitory phosphate. The dephosphorylation reaction, coupled with the addition of the activating phosphate, changes the Cdk’s shape in a way that turns on its kinase activity. Once MPF is active chromosomes condense + spindle apparatus starts to form. How is MPF Turned Off? During anaphase, an enzyme complex begins degrading MPF’s cyclin subunit destruction. 2 Key Concepts about Regulatory Systems in Cells: 1. Negative Feedback occurs when a process is slowed or shut down by one of its products. MPF Is turned off by an enzyme complex that is activated by events in mitosis. 2. Destroying specific proteins is a common way to control cell processes. The enzyme complex attaches small proteins called ubiquitins to MPF’s cyclin subunit. This marks the subunit for destruction by a protein complex called the proteasome. CellCycle Checkpoints Can Arrest the Cell Cycle Cellcycle checkpoint – a critical point where the cell cycle is regulated. o Discovered checkpoints from defects in yeast cell cycle. Cells that keep dividing uncontrollably may form a mass of cells called a tumor. There are distinct checkpoints in three of the four phases of the cell cycle. Chapter 12 – The Cell Cycle MingHan Lu o In effect, interactions among regulatory molecules at each checkpoint allow a cell to “decide” whether to proceed with division or not. If these regulatory molecules are defective, the checkpoint may fail and cells may start dividing in an uncontrolled fashion. G 1Checkpoint Important because it decides whether the cell will continue the cycle to divide or exit the cycle and enter G . o o 4 requirements 1. Size 2. Availability of nutrients 3. Social signals 4. Damage to DNA (if DNA is physically damaged, the protein p53 activates genes that either stop the cell cycle until the damage can be repaired or cause the cell’s programmed, controlled destruction—a phenomenon known as apoptosis. ) If p53 is defective, damaged DNA remains unrepaired. Damage in genes that regulate cell growth can lead to uncontrolled cell division. o Regulatory proteins like p53 are called tumor suppressors. G 2Checkpoint Occurs after S phase, at the boundary between G and 2 phases. o MPF is involved at the G checkpoint 2 If DNA is damaged/chromosomes are not replicated correctly, removal of the inactivating phosphate is blocked. When MPF is not turned on, cells remain in G 2 ase. Cells at this checkpoint may respond to signals from other cells + to internal signals relating to their size. MPhase Checkpoints The final two checkpoints occur during mitosis. 1. The first regulates the onset of anaphase. a. Cells in M phase will not split the chromatids until all kinetochores attach properly to the spindle apparatus. 2. Regulates the progression through M phase into G . If c1romosomes do not fully separate during anaphase, MPF will not decline and the cell will be arrested in M phase. a. Presence of MPF activity prevents the cell from undergoing cytokinesis and exiting the M phase. Chapter 12 – The Cell Cycle MingHan Lu To summarize, the four cellcycle checkpoints have the same purpose: they prevent the division of cells that are damaged or that have other problems. The G checkpoint also 1 prevents mature cells that are in the G s0ate from dividing. 12.5 Cancer: OutofControl Cell Division Cancer – general term for the disease caused by cells that divide in an uncontrolled fashion, invade nearby tissues, and spread to other sites in the body. Cancers arise from cells in which cellcycle checkpoints have failed. Cancerous cells have two types of defects related to cell cell division: 1. Defects that make the proteins required for cell growth active when they shouldn’t be, and 2. Defects that prevent tumor suppressor genes from shutting down the cell cycle. o Defective Ras proteins/tumor suppressor p53 Properties of Cancer Cells Cancer cells are invasive—meaning that they are able to spread to adjacent tissues and throughout the body via the bloodstream/the lymphatic vessels, which collect excess fluid from tissues and return it to the bloodstream. o Invasiveness is a defining feature of a malignant tumor—one that is cancerous. o Masses of noninvasive cells are noncancerous and form benign tumors. Cells become malignant and cancerous if they gain the ability to detach from the original tumor and invade other tissues. o Establishing secondary tumors elsewhere in the body = metastasis Cancer Involves Loss of CellCycle Control Many types of cancer involve defects in the G che1kpoint. Social Control In unicellular organisms, passage through the G checkpoint is thought to 1 depend primarily on cell size and the availability of nutrients. In multicellular organisms, cells divide in response to signals from other cells. Biologists refer to this as social control over cell division. The general idea is that individual cells should be allowed to divide only when their growth is in the best interests of the organism as a whole. o Social control of the cell cycle is based on growth factors – polypeptides or small proteins that stimulate cell division. Cells w/ adequate nutrition are arrested in G p1ase, but when added serum (the liquid portion of blood that remains after blood Chapter 12 – The Cell Cycle MingHan Lu cells and cell fragments have been removed), it allowed cells to pass through the G ch1ckpoint. Cancer cells are an exception. They can be cultured successfully without externally supplied growth factors. How does the G Che1kpoint Work? In G 0cells, the arrival of growth factors stimulates the production of a key regulatory protein called E2F. When E2F is activated, it triggers the expression of genes required for S phase. When E2F is first produced, its activity is blocked by a tumor suppressor protein called Rb. Rb protein (retinoblastoma) is one of the key molecules that enforces the G c1eckpoint. When E2F is bound to Rb, it is in the “off” position – it can’t activate the genes required for S phase. o As long as Rb stays bound to E2F, the cell remains in G . 0 Situation changes dramatically if growth factors continue to arrive. As in passage from G to2M phase, phosphorylation of other proteins catalyzed by an activated cyclinCdk dimer permits passage from G to S 1hase. Step 1 – Growth factors arrive from other cells Step 2 – The growth factors stimulate the production of E2F and of G cyclins, which 1 are different from those used in MPF. Step 3 – Rb binds to E2F, inactivating it. The G cy1lins begin forming cyclinCdk dimers. Initially, the Cdk component is phosphorylated and inactive. Step 4 – When dephosphorylation turns on the the G cyclin1Cdk complexes, they catalyze the phosphorylation of Rb. Step 5 – The phosphorylated Rb changes shape and releases E2F. Step 6 – The unbound E2F is free to activate its target genes. Production of Sphase proteins gets S phase under way. In this way, growth factors function as a social signal that says, “it’s okay to override Rb. Go ahead and pass the G chec1point and divide.” How Do Social Controls and CellCycle Checkpoints Fail? Cells can become cancerous when social controls fail—meaning, when cells begin dividing in the absence of the goahead signal from growth factors. 2 two things can happen: G cycl1 is overproduced, or Rb is defective. o When cyclins are overproduced and stay at high concentrations, the Cdk that binds to cyclin phosphorylates Rb continuously. This activates E2F and sends the cell into the S phase. Cyclin overproduction results from (1) excessive amounts of growth factors or (2) cyclin production in the absence of growth signals. Chapter 12 – The Cell Cycle MingHan Lu This pathway includes the Ras protein, it is common to find overactive Ras proteins in cancerous cells. What happens if Rb is defective? When Rb is missing or does not bind normally to E2F, any E2F that is present pushes the cell through the G1 checkpoint and into the S phase, leading to uncontrolled cell division.
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