1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education contents Principles of Biology 33 Cell Cycle Control Molecular controls monitor the progression of the cell cycle. Cancer occurs when the cell cycle checkpoints somehow fail, which causes cells to divide out of control. The breast cancer cells above have become cancerous and have divided excessively throughout the breast tissue. This breast tissue is stained with dyes to show nuclei clearly (magnified 200X). Dr. Cecil Fox/National Cancer Institute. Topics Covered in this Module Overview of Cell Cycle Regulation Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle There Are Many Cyclins in Cells Major Objectives of this Module Describe the molecular system that regulates progression through the cell cycle. Describe how cell cycle control mechanisms respond to internal and external signals. Explain how cancers result from breakdowns in cell cycle control. page 174 of 989 5 pages left in this module http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058#bookContentViewAreaDivID 1/1 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education contents Principles of Biology 33 Cell Cycle Control Overview of Cell Cycle Regulation In a human adult, skin cells divide continuously, whereas liver cells divide only in response to injury, and muscle cells repair themselves but cannot divide. Cells clearly differ in their ability to divide continuously, occasionally, or never again after being formed. Why? What tells a cell whether to progress through the cell cycle or stop? In the 1970s, scientists investigated this question by fusing cells in culture that were in different stages of the cell cycle. If one cell was in G1 and the other in S, the G1 cell's nucleus began synthesizing DNA just like the second cell's nucleus. If one cell was in G1 and the other in mitosis, the G1 nucleus went straight into mitosis (Figure 1). What could this mean? The scientists hypothesized that signals in the cytoplasm were instructing the nucleus what to do. Figure 1: Cell cycle controls. Fusing a dividing cell with a cell at rest causes the resting cell to enter cell division. Human cells in the G1, S, or G2 phase are fused with cells in the M phase. Premature chromosome condensation can be seen when a cell in the M phase is fused with a) one cell in the G1 phase or b) two cells in the G1 phase. Premature chromosome condensation occurs when an M­phase cell is fused with c) an S­phase cell and d) when a cell is blocked at the G1­S boundary by chemical treatment. Premature chromosome condensation is observed in e) an M­ phase cell fused with a cell in the G2 phase. In panel f) the chromosomes show characteristics of all three original cells when a cell is formed from the fusion of three cells in the G1, G2, and M phases. (Notice the arrows. G1 chromosomes are thin threads, G2 chromosomes are thicker and more condensed, and M chromosomes are short, thick, and rod­ like). © 1970 Nature Publishing Group Johnson, R.T. & Rao, P.N., Mammalian cell fusion: induction of premature hromosome condensation in interphase nuclei. Nature 226, 717–722 (1970) doi: 10.1038/226717a0. Used with permission. Figure Detail Research has since revealed that external signals as well as molecular signals within the cell can move a cell into a later phase of its cycle or cause it to pause. The system that controls which phase a cell is in is called the cell cycle control system. The times at which the cycle can be stopped or pushed forward are called checkpoints. By default, animal cells stop at the checkpoint, the way you would stop at the stadium gate on the way into a game or concert. Once the ushers know that you have a valid ticket, and you're not a danger to the rest of the crowd, they let you enter. Protein signaling pathways are the ushers that interact with molecules involved in the cell cycle, such as components of the DNA replication machinery and microtubules, to decide whether or not a cell should continue. If all the cellular processes that need to be completed before proceeding have been completed successfully and the environment seems favorable, then the cell passes through the checkpoint to the next phase. At these checkpoints in the cell cycle, existing conditions are considered and the cell decides whether it is safe to proceed or stop and not divide (Figure 2). Checkpoints are at G1 (before the cell copies its DNA), G2 (before it enters mitosis), and M (before the sister chromatids separate), among other points. The most important checkpoint in mammals seems to be the G1 checkpoint. If the cell is not given the go­ahead at this point, it goes into G0 phase and stops dividing. Most highly differentiated cells in the human body, including mature muscle cells and neurons, remain in G0. http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/1 1/3 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education Some cells, like liver cells, can leave G0 and reenter the cycle to repair an injury. If a cell passes through a G1 checkpoint, it usually goes on to complete mitosis. Growth and repair happen as needed. In some cases, such as in the liver, even if half of the organ is removed or damaged the remaining cells will divide to regenerate the whole organ. Figure 2: Cell cycle regulation. For a cell to proceed through the phases of the cell cycle, certain protein signaling pathways must proceed to completion. The requirements for these pathways can be thought of as "checkpoints." These checkpoints prevent cells from reproducing under certain circumstances, such as if cells are injured, experience a malfunction during the stages of reproduction, or are not meant to reproduce. © 2012 Nature Education All rights reserved. Figure Detail IN THIS MODULE Overview of Cell Cycle Regulation Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle There Are Many Cyclins in Cells Summary Test Your Knowledge WHY DOES THIS TOPIC MATTER? Cancer: What's Old Is New Again Is cancer ancient, or is it largely a product of modern times? Can cutting­edge research lead to prevention and treatment strategies that could make cancer obsolete? Stem Cells Stem cells are powerful tools in biology and medicine. What can scientists do with these cells and their incredible potential? PRIMARY LITERATURE The memory of iPS cells Incomplete DNA methylation underlies a transcriptional memory of somatic cells in http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/1 2/3 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education human iPS cells. View | Download Genetically­matched iPS cells more immunogenic than ES cells Immunogenicity of induced pluripotent stem cells. View | Download Adaptor proteins regulate cell signaling Structural basis for regulation of the Crk signaling protein by a proline switch. View | Download The role of cyclin D1 in DNA repair linked to cancer growth A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. View | Download SCIENCE ON THE WEB Follow the Cell Cycle An animated diagram of the cell cycle The Nitty­gritty of Cell Cycle Control Read a Scitable article on cell cycle control and cancer Targeted Therapy Watch a lecture on Gleevec, a cancer therapeutic targeting tyrosine receptor kinases Discover more about p53 Play this interactive to learn about "The Guardian of the Genome" page 175 of 989 4 pages left in this module http://www.nature.com/principles/ebooks/principles­of­biology­104015/29145058/1 3/3 1/20/2015 Cell Cycle Control | Principles of Biology from Nature Education contents Principles of Biology 33 Cell Cycle Control Maturation­promoting Factor Was the First Complex Identified that Controls the Cell Cycle As the experiment in fusing cells indicated, the cell cycle is regulated substantially by proteins in the cell's cytoplasm. Many of the proteins involved in cell cycle regulation are cyclin­dependent kinases (Cdks). A cyclin is a protein whose concentration in the cell varies cyclically. A kinase is an enzyme that catalyzes the addition of a phosphate group to a molecule. Cdks are kinases whose activities are controlled by forming complexes with cyclins. Cyclin­Cdk complexes are formed from a protein kinase subunit and a cyclin subunit. When the two subunits associate, they form what is called the holoenzyme. In most cases, the concentration of the kinase subunit is relatively constant, whereas the concentration of the cyclin subunit oscillates. The kinase is completely inactive without its cyclin partner, but in addition to the formation of the cyclin­Cdk complex, activation of the holoenzyme requires the phosphorylation of a key residue in the kinase subunit. Test Yourself How does the Cyclin­Cdk holoenzyme form, and how is it activated? Submit The first cyclin­Cdk complex discovered — MPF or maturation­promoting factor — was found in frog eggs. The cyclin that is part of MPF is synthesized during the S and G2 phases (Figure 3). During G2, when this cyclin has reached critical concentration, it forms a complex with Cdk, producing MPF. MPF triggers mitosis by phosphorylating proteins, in some cases activating additional enzymes. It phosphorylates proteins in the nuclear envelope, promoting the nuclear envelope's breakdown during prophase. MPF may also help chromosomes to condense and the mitotic spindle to form in prophase. In anaphase, MPF's actions cause its cyclin component to be broken down. The kinase remains in the cell in inactive form until new cyclin molecules are synthesized.