Todo

Cell Prolif. 2003, 36, 131– 149

The cell cycle: a review of regulation, deregulation and
therapeutic targets in cancer
.
K.
Original Article
36 Vermeulen
0960-7722
Cell cycle Publishing Ltd
CPRProliferation
Oxford, UK et al. Ltd.
Blackwell regulation and deregulation

Katrien Vermeulen, Dirk R. Van Bockstaele and Zwi N. Berneman
Faculty of Medicine, Laboratory of ExperimentalHematology, University of Antwerp, Antwerp University Hospital,
Edegem, Belgium
Received 7 May 2003; revision accepted 2 June 2003

Abstract. The cell cycle is controlled by numerous mechanisms ensuring correct cell
division. This review will focus on these mechanisms, i.e. regulation of cyclin-dependent
kinases (CDK) by cyclins, CDK inhibitors and phosphorylating events. The qualitycheckpoints activated after DNA damage are also discussed. The complexity of the
regulation of the cell cycle is also reflected in the different alterations leading to aberrant cell proliferation and development of cancer. Consequently, targeting the cell cycle
in general and CDK in particular presents unique opportunities for drug discovery.
This review provides an overview of deregulation of the cellcycle in cancer. Different
families of known CDK inhibitors acting by ATP competition are also discussed. Currently, at least three compounds with CDK inhibitory activity (flavopiridol, UCN-01,
roscovitine) have entered clinical trials.

GENERAL STRATEGY OF THE CELL CYCLE
Cell division consists of two consecutive processes, mainly characterized by DNA replication
and segregation of replicatedchromosomes into two separate cells. Originally, cell division
was divided into two stages: mitosis (M), i.e. the process of nuclear division; and interphase,
the interlude between two M phases (Fig. 1). Stages of mitosis include prophase, metaphase,
anaphase and telophase. Under the microscope, interphase cells simply grow in size, but different techniques revealed that the interphase includesG1, S and G2 phases (reviewed in Norbury
& Nurse 1992). Replication of DNA occurs in a specific part of the interphase called S phase.
S phase is preceded by a gap called G1 during which the cell is preparing for DNA synthesis
and is followed by a gap called G2 during which the cell prepares for mitosis. G1, S, G2 and M
phases are the traditional subdivisions of the standard cell cycle (Fig.1). Cells in G1 can, before
commitment to DNA replication, enter a resting state called G0. Cells in G0 account for the major
part of the non-growing, non-proliferating cells in the human body.

Correspondence: Zwi N. Berneman, Laboratory of Experimental Hematology, University of Antwerp, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium. Tel.: +32 3821 37 80; Fax: +32 382142 86; E-mail:
zwi.berneman@uza.be
© 2003 Blackwell Publishing Ltd.

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Figure 1. The stages of the cell cycle. The site of activity of regulatory CDK /cyclin complexes is also indicated.

CONTROL OF THE CELL CYCLE
Cyclin-dependent kinase (CDK) regulation
The transition from one cell cycle phase to another occurs in an orderly fashion and is regulated
bydifferent cellular proteins. Key regulatory proteins are the cyclin-dependent kinases (CDK),
a family of serine/threonine protein kinases that are activated at specific points of the cell cycle.
Until now, nine CDK have been identified and, of these, five are active during the cell cycle, i.e.
during G1 (CDK4, CDK6 and CDK2), S (CDK2), G2 and M (CDK1) (Table 1, Fig. 1). When
activated, CDK inducedownstream processes by phosphorylating selected proteins (Morgan
1995; Pines 1995). CDK7 acts in combination with cyclin H as CDK activating kinase (CAK,
see below) (Fisher & Morgan 1994). The remaining CDK have not yet been shown to have a
crucial role in normal cell cycle progression (Rickert et al. 1996). CDK protein levels remain
stable during the cell cycle, in contrast to their...