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4  Control of the Cell Cycle

Marcos Malumbres

• Most cells in postnatal tissues are growth factor or cytokine senescence, or death in response to
quiescent. Exceptions include exposure, cell-to-cell contact, cellular stress.
abundant cells of the hematopoietic and basement membrane • Checkpoints minimize replication
system, skin, and gastrointestinal attachments. and segregation of damaged DNA
mucosa, as well as other minor • The internal cell cycle machinery is or the abnormal segregation of
progenitor populations in other controlled largely by oscillating levels chromosomes to daughter cells,
tissues. of cyclin proteins and by modulation thus protecting cells against genome
• Many quiescent cells can reenter of cyclin-dependent kinase (Cdk) instability.
into the cell cycle with the activity. One way in which growth • Disruption of cell cycle controls
appropriate stimuli, and the control factors regulate cell cycle is a hallmark of all malignant
of this process is essential for tissue progression is by affecting the levels cells. Frequent tumor-associated
homeostasis. of the D-type cyclins, Cdk activity, alterations include aberrations in
• The key challenges for proliferating and the function of the growth factor signaling pathways,
cells are to make an accurate copy retinoblastoma protein. dysregulation of the core cell cycle
of the 3 billion bases of DNA • Cell cycle checkpoints are machinery, and/or disruption of cell
(S phase) and to segregate the surveillance mechanisms that link cycle checkpoint controls.
duplicated chromosomes equally the rate of cell cycle transitions • Because cell cycle control is
into daughter cells (mitosis). to the timely and accurate disrupted in virtually all tumor
• Progression through the cell cycle completion of prior dependent types, the cell cycle machinery
is dependent on both intrinsic events. p53 is a checkpoint protein provides multiple therapeutic
and extrinsic factors, such as that induces cell cycle arrest, opportunities.

INTRODUCTION copy their genomes and segregate them to the daughter cells with
high fidelity. Eukaryotic cells therefore have evolved a series of surveil-
Most cells in the adult body are quiescent—that is, they are bio- lance pathways, termed “cell cycle checkpoints,” that monitor for
chemically and functionally active but do not divide to generate potential problems during the cell cycle process.4 Human cells are
daughter cells. However, specific populations retain the ability to continuously exposed to external agents (e.g., reactive chemicals and
proliferate throughout the adult life span, which is essential for ultraviolet light) and to internal agents (e.g., byproducts of normal
proper tissue homeostasis. For example, cells of the hematopoietic intracellular metabolism, such as reactive oxygen intermediates) that
compartment and the gut have a high rate of turnover, and active can induce DNA damage. The cell cycle checkpoints detect DNA
proliferation is therefore essential for the maintenance of these damage and activate cell cycle arrest and DNA repair mechanisms,
tissues. On average, about 2 trillion cell divisions occur in an adult thereby maintaining genomic integrity.
human every 24 hours (about 25 million per second). The decision Anything that disrupts proper cell cycle progression can lead
about whether to proliferate is tightly regulated.1,2 It is influenced by to either the reduction or expansion of a particular cell population.
a variety of exogenous signals, including nutrients and growth It is now clear that such changes are a hallmark of tumor cells,
factors, as well inhibitory factors and the interaction of the cell with which carry mutations that impair signaling pathways; that is, they
its neighbors and with the underlying extracellular matrix. Each of suppress proliferation and/or activate pathways that promote pro-
these factors stimulates intracellular signaling pathways that can liferation. In addition, most (if not all) human tumor cells have
either promote or suppress proliferation. The cell integrates all of mutations within key components of both the cell cycle machinery
these signals, and if the balance is favorable, the cell will initiate the and checkpoint pathways.1,5,6 This characteristic has important
proliferation process. clinical implications, because the presence of these defects can
During the past three decades, extensive effort has been placed on modulate cellular sensitivity to chemotherapeutic regimens that
unraveling the basic molecular events that control this process. induce DNA damage or mitotic catastrophe. This chapter focuses
Studies in a variety of organisms have identified evolutionarily con- on the mechanics of the cell cycle and checkpoint-signaling path-
served machinery that controls eukaryotic cell cycle transitions ways and discusses how this knowledge can lead to the efficient
through the action of key enzymes, including cyclin-dependent use of current anticancer therapies and to the development of
kinases (Cdks) and other kinases.3 It is essential that proliferating cells novel agents.