Cell Cycle Regulators

9 Key excerpts on "Cell Cycle Regulators"

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  eBook - ePub

  Understanding Cancer

  From Basics to Therapeutics

  • Buddhi Prakash Jain, Shweta Pandey, Buddhi Prakash Jain, Shweta Pandey(Authors)
  • 2022(Publication Date)
  • Academic Press

    (Publisher)

  Chapter 6

  Cancer and cell cycle

  Rohini R., Naira , Suresh S., Yadavb

  a Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

  b Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

  Abstract

  Cell homeostasis is maintained by a balanced regulation of cell growth, cell proliferation, and cell death. Several cell cycle checkpoints tightly regulate the division of cells. Defects in these checkpoints may lead to the accumulation of genomic abnormalities resulting in a pathological condition, such as cancer. Cancer is characterized by the uncontrolled cell proliferation due to various defects at the genetic and molecular levels, including the aberrant activity of several proteins involved in the cell cycle checkpoints regulation. Therefore, the cell cycle regulatory proteins are considered to be the most attractive targets in the cancer therapy. After extensive research of decades on the physiological functions and regulation of cell cycle proteins, several Cell Cycle Regulators are being targeted for the cancer therapy. Here in this chapter, we will discuss the cell cycle, Cell Cycle Regulators, and the significance of targeting them for the cancer therapeutics.

  Keywords

  Cell cycle; Cell cycle regulation; Check points; DNA damage; Cancer therapeutics

  6.1 Introduction

  Cancer is defined as a pathological condition, where the cells divide in an uncontrolled manner. The development of cancer is a long process and starts with some genetic and tissue micro-environmental changes in the respective organ. In normal tissues, healthy cells receive a signal to die after a particular time and are replaced with the new cells. Cancerous cells lack this mechanism, resulting in its continuous division. The signals from the neighboring cells and the ability to respond to it, play a crucial role in the cell division and cancer progression.

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  eBook - ePub

  Cellular Signal Processing

  An Introduction to the Molecular Mechanisms of Signal Transduction

  • Friedrich Marks, Ursula Klingmüller, Karin Müller-Decker(Authors)
  • 2017(Publication Date)
  • Garland Science

    (Publisher)

  Section 12.8 ). By this means, dissemination of harmful mutations is prevented. However, as is typical for data processing, this control is not perfect but may be evaded, in particular in the course of tumorigenesis.

  Figure 12.1 Mammalian cell cycle Phases of the cell cycle: S, synthesis phase, period of DNA replication; M, mitosis phase, period of chromosome separation and cytokinesis; G1 and G2, so-called gap phases, where the cell realizes specific programs of differentiation and prepares for DNA replication and mitosis, respectively; G0, resting phase; upon mitogenic stimulation the cell may return to the cell cycle. The three major checkpoints are shown in teal.

  Figure 12.2 Cyclin levels and cyclin-dependent kinase activities during the cell cycle (A) Cyclin–CDK activities associated with the individual phases. (B) Oscillation of the cyclin level (teal curve) and the CDK activity (colored bars) depending on the cell cycle phase as represented by the DNA content (black line and ordinate). As an example, the cyclin B–CDK1 pair has been chosen.

  The amazing precision of the cell cycle is guaranteed by control elements meshing like gears. In this mechanism, strictly regulated formation and degradation of regulatory proteins together with precisely timed protein phosphorylation play a key role. The master regulators of cell cycle progression are the cyclin-dependent protein kinases (CDKs). Their importance was discovered originally by studies on yeast mutants with defective or overexpressed cdc (cell division cycle) genes* and on starfish and amphibian oocytes.

  To make a fertilized egg, the cell cycle of oocytes is arrested at the G2–M transition. This arrest could be overcome by progesterone or by a maturation-promoting factor (MPF) isolated from dividing frog cells. MPF was identified as a protein kinase in the late 1980s. A homologous kinase was found to be encoded by the yeast cdc gene number 2. Both kinases were originally called Cdc2 but today are known as CDK1. They turned out to be the catalytic subunits of a complex with a regulatory protein called cyclin B. Cyclin B appeared in the G2 phase to stimulate CDK1 and then disappeared abruptly at the end of the M phase. In contrast, Cdc2 (CDK1) was always present but was active only in the presence of cyclin B (Figure 12.2

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  The Molecular Basis of Cancer E-Book

  The Molecular Basis of Cancer E-Book

  • John Mendelsohn, Peter M. Howley, Mark A. Israel, Joe W. Gray, Craig B. Thompson(Authors)
  • 2014(Publication Date)
  • Saunders

    (Publisher)

  11

  Regulation of the Cell Cycle

  Yan Li

  ,

  Olena Barbash

  , and

  J. Alan Diehl

  Basic Principles of Cell Cycle Progression

  The essential function of cell cycle control is the regulated duplication of the cells’ genetic blueprint and the division of this genetic material such that one copy is provided to each daughter cell following division. The cell cycle can be divided conceptually into four individual phases. The “business” phases include S phase or synthesis phase, which is the period during which DNA is replicated, and mitosis (M phase ), where DNA is packaged, the cells divide, and DNA is distributed to daughter cells. S phase and M phase are separated by Gap phases (G phase) to provide the cell with a proofreading period to ensure that DNA replication is completed and packaged appropriately prior to division. Separating M phase from S phase is the first Gap phase (G1 phase) and separating S phase from M phase is the second Gap phase (G2 phase).

  G0

  or quiescence occurs when cells exit the cell cycle because of the absence of growth-promoting signals or the presence of prodifferentiation signals. Ordered progression through each phase is intricately regulated through both positive and negative regulatory signaling molecules and is the basis of normal organismal development. The consequences of deregulated growth control include failed or altered development and/or neoplastic/cancerous growth. Over the past two decades, a detailed picture of the major regulators of cell cycle control in both model organisms and higher eukaryotes has evolved. In this chapter, we describe the major regulators of cell division control and introduce current concepts regarding their participation in cell growth.

  The Cyclin-Dependent Kinases

  Cell cycle progression is positively regulated by a family of protein kinases referred to as the cyclin-dependent kinases (CDKs). In yeast, the organism in which early groundbreaking work defined many major Cell Cycle Regulators, a single CDK regulates cell division: CDC2 (Schizosaccharomyces pombe , fission yeast) and CDC28 (Saccharomyces cerevisiae , budding yeast). In contrast, multicellular organisms use a distinct CDK whose activity promotes transition through each cell cycle phase (Figure 11-1 ). CDKs are binary enzymes. The catalytic subunit, the CDK, coordinates adenosine triphosphate (ATP) and transfers phosphate to appropriate substrates. As a monomer, the CDK has no enzymatic activity; activation requires association with a specific allosteric activator called a cyclin. CDK subunits associate with specific cyclins (Table 11-1

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  eBook - ePub

  Biochemistry of Signal Transduction and Regulation

  • Gerhard Krauss(Author)
  • 2014(Publication Date)
  • Wiley-VCH

    (Publisher)

  The different phases of the cell cycle include a number of highly ordered processes that ultimately lead to duplication of the cell. The various cell-cycle events are highly coordinated to occur in a defined order and with an exact timing, requiring precise control mechanisms.

  A biochemical system is at the center of the cell cycle, of which the most important players are Ser/Thr-specific protein kinases and regulatory proteins associated with these. The activity of this central cell-cycle “engine” regulates processes downstream that help to carry out the many phase-specific biochemical reactions of the cell cycle in a defined order. Furthermore, the system has built-in feedback mechanisms and allows for linkages between events that are not immediately consecutive in the cycle. In this way, it is ensured that the phases of the cell cycle are executed completely and in the correct sequence.

  Intrinsic controls of the cell cycle:

  • Completion of phases
  • Correct order of phases
  • Adequate cell size

  Three aspects of the cell cycle are central to its function and control:

  • Cell growth: Cells must accumulate enough cell mass and organelles to establish two daughter cells.
  • Survival: Cells must receive or produce survival signals that help to prevent programmed cell death (apoptosis). As an example, a balance of cell death and compensatory proliferation maintains the epithelia in a state of constant renewal.
  • Proliferation: Cells must be instructed by the environment to divide at a given place and a given time. Proliferation-promoting signals are received by cells almost exclusively during G1

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  eBook - ePub

  Upstream Industrial Biotechnology, 2 Volume Set

  • Michael C. Flickinger(Author)
  • 2013(Publication Date)
  • Wiley

    (Publisher)

  Chapter 5: Cell Cycle in Bioprocesses Mariam Naciri and Mohamed Al-rubeai University College Dublin, Belfield, Dublin, Ireland The cell cycle is the name given to the process by which a cell matures, synthesizes DNA, and divides to form daughter cells. Thus the cell cycle is a fundamental process with analogous mechanisms found in all cells, from the most primitive bacterium to higher animals and plants, from the unicellular to the most complex multicellular organism. It is regulated by several ordered and directional molecular events and controlled by an elaborate system that if altered could result in physiological damage and cell death (1). Here we describe the mammalian cell cycle, highlight its importance in biotechnology, and describe some cell cycle applications in animal cell biotechnology. mammalian cell cycle; cell division; mitosis; flow cytometry; product expression 5.1 Introduction The cell cycle model (G 1 -event model) currently accepted by authors of the major cell and molecular biology books (2–5) describes the cell cycle as discrete phases controlled by cell cycle proteins interacting with each other and directing cellular events including DNA synthesis and cell division. However, the validity of this model and the interpretation of many experiments that underpin the current established view of the cell cycle and its regulation have been questioned (6, 7). The proposed alternative, the continuum model, suggests that the cell cycle does not exist as currently recognized but takes the form of a continuum from one cell division to the next, rather than discrete phases with discrete groups of regulatory proteins. A hypothetical initiator of DNA replication is synthesized by the cell during all phases of the cell cycle, and its concentration reaches a critical level that initiates DNA synthesis. Thus the cell can control its rate of division by regulating the amount of initiator

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  eBook - ePub

  Rediscovering Cancer: From Mechanism to Therapy

  • Sayali Mukherjee, Somali Sanyal, Sonia Chadha, Sayali Mukherjee, Somali Sanyal, Sonia Chadha(Authors)
  • 2018(Publication Date)
  • Apple Academic Press

    (Publisher)

  The cell cycle is an exceptionally structured physiological mechanism governing the duplication and transmission of hereditary genetic material from one cell generation to the next and therefore requires control. Accurate control of this cyclical progression at different “checkpoints” is fundamental for deciding when a cell ought to focus on deoxyribonucleic acid (DNA) synthesis and division versus proliferation arrest, DNA repair, or apoptosis. Ideally, checkpoints delay transition from one cell cycle phase to another by a complex system of positive and negative regulatory mechanisms, until the specific endogenous or exogenous condition has been satisfied. Inappropriate cell proliferation that bypasses normal cell checkpoints is the hallmark of cancer cells. The gain-of-function mutations in oncogenes and loss-offunctions in tumor suppressor genes were initially shown to contribute to cancer development. Recent studies have focused on the signaling pathways of cell cycle regulatory genes in the hope of modulating cancer progression. However, it is not clearly understood, exactly how does single (or even multiple) gene sequence modifications, translational upregulation, or obliterated regulatory domains influence the mechanism of cell cycle. Therefore, understanding the underlying regulatory signaling networks may give us knowledge on the parity of a typical cell cycle and carcinogenic cell expansion and recommend techniques for disease treatment.

  3.1 Introduction

  The sequence of growth and division of a eukaryotic cell into daughter cells can be described as a series of coordinated events that compose a “cell division cycle.” The process starts with the cell triggered to enter the cell cycle, followed by genetic material synthesis, equal partitioning, and cleavage of the cell during cytokinesis. In 1950–1960s, Alma Howard’s and Stephen Pelc’s pioneering work in broad bean, Vicia faba , further revealed that during this cyclical division, a cell goes through discrete phases that can be broadly identified as follows: the interphase [consisting of gap 1 (G1), DNA synthesis (S), and gap 2 (G2)] and mitosis (M) phases [1 ]. Entry into the cycle from a previous mitotic cycle is made during G1, followed in sequence by DNA synthesis in the S phase; time lapse between synthesis and division is the G2 phase, and subsequently, genetic material division occurs during the M phase. To maintain this cell cycle integrity, cells are governed by a complex network of control system popularly known as “checkpoints.” Both intracellular and extracellular signals control cyclical progression by modulating these checkpoints. Thus, depending upon the signals received, when a cell fails to complete a crucial stage of cell cycle or experiences unfavorable conditions, the cell cycle progression can either be arrested or be diverged at the start of G1 into a quiescent nondividing phase called G0 (gap zero). These molecular checkpoints are functionally classified as follows: first, a cascade of protein kinases that modulate cell cycle progression and second, an arrangement of flagging checkpoints that screen finishing of critical stages and even defer movement to the following stage if necessary. Principal among the cell cycle control mechanisms are a group of serine/threonine kinases, known as cyclin-dependent kinases (CDKs) and their modulator cyclin subunits. These kinases are in turn regulated further regulated by binding of cyclin-dependent kinase inhibitors (CKIs) as well as by a host of post-translational modifications. Moreover, transcriptional control by intrinsic and extrinsic factors limits cyclin production to specific phases of the cell cycle. The ubiquitin-mediated proteolysis of cyclin further guarantees irreversible inactivation of the related CDK. This periodicity of the cyclins, regulated by their synthesis and proteolytic degradation, gives the cell unique control over advancement from one cycle to the next [2

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  eBook - ePub

  Advanced Molecular Biology

  A Concise Reference

  • Richard Twyman(Author)
  • 2018(Publication Date)
  • Garland Science

    (Publisher)

  completion of DNA replication, and replication commences after mitosis has precisely divided the DNA. The cell meets these criteria by organizing the cell cycle as a dependent series of events. Thus, if mitosis is blocked, the cell cycle arrests at the M phase until the block is removed — it does not go ahead and replicate the DNA anyway (i.e. DNA replication is dependent upon the completion of mitosis). Similarly, if DNA replication is prevented, the cell does not attempt to undergo mitosis, because mitosis is dependent upon the completion of DNA replication.

  A further function of the cell cycle is to coordinate the chromosome cycle with cell growth, so there is no progressive loss or gain of cytoplasm, and no cell proliferation in an unsuitable environment. Progress through the cell cycle is thus also dependent upon cell size and is regulated by nutrient availability, the presence of mating pheromones (in yeast), and the presence of growth factors and hormones (in animals).

  The cell possesses a number of regulatory systems which can sense the progress of the cell cycle and can inhibit subsequent stages in the event of failure. These regulatory mechanisms are termed cell cycle checkpoints, and represent intrinsic signaling systems of cell cycle control. The checkpoint mechanisms also respond to external signals so that arrest may occur in cases of nutrient deprivation or growth factor withdrawal. There are numerous checkpoints in the cell cycle, which are clustered in two major groups — those occurring at G1 and regulating entry into the S phase, and those occurring at G2 and regulating entry into the M phase (Figure 2.2 ). This clustering suggests that intrinsic and extrinsic signals may funnel into common components of cell cycle regulation. Additional checkpoints insure the orderly and dependent series of events which comprise mitosis.

  Figure 2.2:

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  Signal Transduction in Cancer

  • Mohamed A. Selmy(Author)
  • 2019(Publication Date)
  • Delve Publishing

    (Publisher)

  Cell Cycle Control 89 Figure. 33 Schematic representation of mitosis (Silkworth and Cimini, 2012) Mitosis is distributed in five phases (Figure. 33): • Prophase: chromatin is condensed into chromosomes; centrosomes, duplicated throughout the G2 phase, are organized and work as nucleation origins for microtubules. • Prometaphase: the nuclear envelope is disrupted, the centrosomes migrate at the two cellular poles and the microtubules are organized as a spindle where chromosomes are attached, at the level of their kinetochore. • Metaphase: chromosomes align at half-distance of the two cellular poles, on an ‘equatorial plate’, after they have been taken by the microtubules. • Anaphase: the homologous chromosomes quit the equatorial plate after deactivation of cohesins and activation of the separase complex enabled by the degradation of securin in the proteasome, where it is driven by the APC/C–CDC20 (anaphase-promoting complex/cyclosome–cell division cycle 20) complex; homologous chromosomes migrate in opposite directions to the poles. • Telophase: the two copies of the genome spread at each pole of the cell, the nuclear envelope is reformed and a tightening takes place between the two nuclei. Signal Transduction in Cancer 90 • Cytodieresis: a contractile actin ring is assembled at half-distance of the two poles and tightens the equatorial zone. This process allows the separation of the daughter cells. 7.2. EFFECTOR PROTEINS OF CELL CYCLE REGULATION 7.2.1. Cyclins and Cyclin-Dependent Kinases Cyclins (CCNs) are proteins of 35–90 kDa with no catalytic activity, but crucial to the activity of serine/threonine kinases which are therefore named cyclin-dependent kinases (CDKs). They are established in two central symmetric domains including five α helices. One of these domains (cyclin box) is highly preserved and signifies the structural characteristic of these proteins.

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  eBook - ePub

  Anticancer Drug Development

  • Bruce C. Baguley, David J. Kerr(Authors)
  • 2001(Publication Date)
  • Academic Press

    (Publisher)

  New avenues for tumor-specific therapeutic intervention are now at close reach. The molecular characterization of tumors should identify the specific defects that drive cell cycle progression in particular cancers and provide us with a rationale for the type of treatment that would be most appropriate for a particular patient. New therapeutic approaches can now be validated genetically (e.g., gene knockout, antisense strategy, gene transfer) prior to a search for (a screening for) small-molecule inhibitors and for validating the activity of such inhibitors against a biochemical target in a given pathway. We will outline the molecular pathways that drive cell cycle progression and regulate the cell cycle checkpoints. We will next address the rationale for developing therapeutics that interfere with cell cycle progression and cell cycle checkpoint. Finally, we will review the various therapeutic approaches that are being developed for cancer treatment. This chapter will focus on the potential therapeutic aspects of the regulation of the G 1 /S and G 2 /M transition. 2. Molecular Regulation of Cell Cycle Progression Cellular proliferation and division requires an orderly progression through the cell cycle, primarily driven by protein complexes composed of cyclins and cyclin-dependent kinases (Cdks) (Fig. 1). Initiation of the cell cycle takes place when cells pass the “restriction point,” as defined by Arthur Pardee 30 years ago (Pardee, 1974), after which cells are committed to complete their cell cycle progression. Progression through the G 1 -S transition requires the activity of at least two different types of kinases, cyclin D-Cdk4/6 and cyclin E/A-Cdk2 (Figs. 1 and 2). (For Fig. 2, see color insert.) At the G 1 -S transition, Cdk4/6 and Cdk2 govern the entry into S phase. Cdk2 continues to be active through S phase, with its decline in activity signaling exit from S phase. Lastly, Cdk1 (Cdc2) becomes active in G 2 and its activity persists through mitosis (Figs

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