Milestones in cell division

To cycle or not to cycle: a critical decision in cancer

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Abstract

Tumour cells undergo uncontrolled proliferation, yet tumours most often originate from adult tissues, in which most cells are quiescent. So, the proliferative advantage of tumour cells arises from their ability to bypass quiescence. This can be due to increased mitogenic signalling and/or alterations that lower the threshold required for cell-cycle commitment. Understanding the molecular mechanisms that underlie this commitment should provide important insights into how normal cells become tumorigenic and how new anticancer strategies can be devised.

Key Points

  • The cell cycle is regulated by cyclin-dependent kinases (CDKs), which form active heterodimeric kinases when bound to the cyclins. Active CDK–cyclin complexes can be negatively regulated by two families of inhibitors, the INK4 and the WAF1/KIP proteins.

  • The CDK4/6–cyclin-D and CDK2–cyclin-E complexes are active in G1, and CDK2–cyclin-A and CDK1–cyclin-A are active in S phase. The CDK complex responsible for driving cells through mitosis is CDK1–cyclin B.

  • The main G1 substrates of CDKs are the retinoblastoma family (RB, p107 and p130). RB is sequentially phosphorylated by CDK4/6–cyclin-D and CDK2–cyclin-E complexes. This phosphorylation inactivates the growth-suppression properties of RB and stimulates progression through G1 and into S phase.

  • The basic regulators of G1 progression are altered in most human cancers. Genetic alterations usually affect CDK4 and CDK6, their positive (mainly cyclin D1) and negative (INK4A and INK4B) regulators and their substrates (mainly RB).

  • Deregulation of CDK2 activity frequently results from the alteration in the expression levels of its regulators cyclin E and KIP1. The cause of these alterations is not clear. Recently, some members of the proteolysis pathways involved in the control of cyclin E and KIP1 protein levels have been found to be altered in certain types of cancer.

  • A few other cell-cycle regulators, mostly those involved in the mitotic spindle checkpoint, are also deregulated in human cancer. They include BUB proteins, MAD2, the Aurora kinases, PLK1 and securin. The evidence for their involvement in human cancer is, so far, scarce.

  • The generation of gene-targeted mice has illustrated the importance of G1 regulators in tumour development. Although most of these are not essential for cell-cycle progression or mouse development, their deregulation often leads to tumour development.

  • The understanding of G1 regulation has opened new avenues to search for antitumor drugs. Although there are several ways to control CDK activity, small-molecule CDK inhibitors are the preferred tools, at this time. So far, several CDK inhibitors (mainly CDK2 and pan-CDK inhibitors) are in advanced preclinical studies and at least two of them — flavopiridol and UCN-01 — have reached clinical trials.

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Figure 1: Regulation of G1 and the G1/S transition.
Figure 2: Mutation of G1/S regulators in human cancer.
Figure 3: CDK regulation and opportunities for therapeutic intervention.

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cyclin D1

cyclin D2

cyclin D3

cyclin E1

cyclin E2

cyclin H

DP

e1F4E

E2F

ERK

GSK-3β

INK4A

INK4B

INK4C

INK4D

IR

IRS

KIP1

KIP2

Lats1

LATS1

MAD2

MAPK

MNK1

MYT1

Neu

p107

p130

p300

p53

PI3K

PKB

PLK1

PP1

RAF

RAS

RB

SKP2

TOR

Waf1

WAF1

WEE1

FURTHER INFORMATION

BioMedNet Mouse Knockout & Mutation Database

CancerNet

CenterWatch

Database of pRb-binding proteins

TBASE (The Transgenic/Targeted Mutation Database)

Glossary

METAZOANS

The kingdom Animalia (animals) that consists of roughly 35 phyla of multicellular organisms.

T LOOP

A short peptide sequence — located between subdomains VII and VIII of protein kinases — that folds as a loop. Phosphorylation might alter its conformation and, hence, the catalytic activity of the protein kinases.

RAS/RAF/MAPK PATHWAY

Signal-transduction pathway that is crucial for the integration of mitogenic signals mediated by a variety of growth factors. Activation of this pathway is involved in many cellular processes, including cell-cycle progression.

SCF UBIQUITIN LIGASE

Multiprotein complex that ligates ubiquitin to proteins that will be degraded by the proteasome. SCF complexes consist of three core subunits (SKP1, CUL1 and RBX1) coupled to one of the several F-box proteins that recognize the protein to be ubiquitylated.

RAS/PI3K/AKT PATHWAY

Signal-transduction pathway that is involved in many cellular processes, such as cell proliferation and apoptosis. Several members of this pathway have oncogenic or tumour-suppressor activities (for example, RAS, PI3K and PTEN).

DOMINANT-NEGATIVE MUTANT

A non-functional mutant protein that competes with the normal, non-mutated protein, blocking its activity.

PROTEASOME

A 26S multiprotein complex that catalyzes the breakdown of polyubiquitylated proteins.

F-BOX PROTEIN

Component of the machinery for the ubiquitin-dependent degradation of proteins. F-box proteins recognize specific substrates and present them to the SCF complex and the proteasome machinery.

ORGANOMEGALY

A phenotype characterized by organs of abnormally large size.

HAPLO-INSUFFICIENCY

A phenotype that arises in diploid organisms due to the loss of only one allele.

PAN-CDK INHIBITORS

CDK inhibitors that do not discriminate between different CDKs. These drugs can frequently inhibit other protein kinases.

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