Cell cycle involves DNA replication and cell
separation. This extremely accurate and orderly process consists of four
distinct phases: G1 phase, S phase, G2 phase, and M phase. Two key classes of
regulatory molecules, the cyclins and the cyclin-dependent kinases (CDKs), play
major roles in cell cycle. At the end of each step of the cell cycle, there is a
checkpoint to verify that every requirement has been met before the cell cycle
is allowed to proceed to the next step. See details here.
G0 phase is a resting phase where cell leaves cell cycle and stops replicating.
These non-proliferative cells are either quiescent or senescent cells. G1, S,
and G2 phases combined are called interphase, during which the cell grows,
accumulates nutrients, and duplicates DNA. M phase is a mitotic phase, during
which the cell splits itself into two daughter cells. M phase includes nuclear
division (karyokinesis) and cytoplasmic division (cytokinesis) and the whole
process can be divided into prophase, prometaphase, metaphase, anaphase, and
telophase.
Cyclins are so called because their expression rises and falls within one
cell cycle and repeats again in the next cell cycle. CDKs are activated upon the
binding of a cyclin. Different cyclin and CDK combinations determine their
downstream targeted proteins. CDKs are constitutively expressed in cells whereas
cyclins are synthesized and degraded at specific stages of the cell cycle. The
cyclins include cyclin A, B, C, D, E, F, G, H, K, and T. Cyclin A, B, D and E
are particularly important in cell cycle.
Animal cells contain at least nine CDKs, however, only four of which (CDK1,
2, 4, and 6) are involved directly in cell cycle control. CDK4 and CDK6 are
important in regulating entry into the cell cycle; CDK1 and CDK2 operate
primarily in M phase and S phase, respectively. CDK7 contributes to cell cycle
indirectly by acting as a CDK-activating kinase (CAK) that phosphorylates other
CDKs. CDKs are also components of the machinery that controls basal gene
transcription by RNA polymerase II (CDK7, 8, and 9) and are involved in
controlling the differentiation of nerve cells (CDK5).
Cyclin D / CDK4, cyclin D / CDK6, and cyclin E / CDK2 complexes regulate
transition from G1 to S phase; the cyclin B / CDK1 complex regulates transition
from S to G2 phase. The most characterized substrate of CDK4/6 and cyclin D
complex is the retinoblastoma tumor suppressor (Rb). During early G1, Rb becomes
phosphorylated and this leads to disassociation of the complex with the histone
deacetylase protein (HDAC) and release of the transcription factors E2F-1 and
DP-1, which positively regulate the transcription of genes whose products are
required for S phase progression, including cyclin A and cyclin E. Rb remains
hyperphosphorylated for the remainder of the cell cycle and CDK2 / cyclin E
participates in maintaining this hyperphosphorylated state. CDK2 / cyclin E
phosphorylates histone H1 and this activity may be important for chromosome
condensation required during DNA replication. Histone H1 is also a substrate for
cyclin B / CDK1.
Two distinct families of CDK inhibitors, the cip/kip family and the INK4a/ARF
family, have been discovered. The cip/kip family includes p21 (Waf1, Cip1), p27
(Cip2), and p57 (Kip2). The p21 gene promoter contains a p53 binding site and
can be activated by p53. p27 is activated by TGF-beta. During G1/S, the CDK2 /
cyclin E complex also phosphorylates its inhibitor p27, inducing its proteasome-dependent
degradation. The INK4a/ARF family includes p16INK4a and p14ARF. p16 binds to
CDK4 and arrests the cell cycle in G1 phase. p14 is an alternate reading frame (ARF)
product of the p16 locus (CDKN2A). p14ARF inhibits mdm2 (which inhibits and
degrades p53), thus activating p53, which activates p21 and therefore halts cell
cycle. Loss of p14ARF by a homozygous mutation in the CDKN2A locus will lead to
elevated levels in mdm2 and, therefore, loss of p53 function and cell cycle
control. Inactivation of one of the two families is an important mechanism
utilized by some types of cancer cells to grow uncontrollably.
One of the most important functions of the checkpoints is to detect DNA
damage. When DNA damage is found, the cell will either repair DNA or go through
apoptosis or other cell death modes. The main checkpoints are G1 (restriction)
checkpoint, G2 checkpoint, and metaphase checkpoint. The G1 checkpoint is the
decision point whether a cell can enter S phase. Many cells stop at this stage
and enter a resting state. This checkpoint is mainly controlled by p16 and Rb.
The G2 checkpoint prevents the cell from entering M phase if proper preparation
has not been achieved. Cyclin B / CDK1 is pivotal in regulating this transition.
p53 plays an important role in triggering the control mechanisms at both G1 and
G2 checkpoints. The metaphase checkpoint (also called mitotic spindle
checkpoint) mainly ensures that all the chromosomes have aligned at the mitotic
plate under bipolar tension.
Deregulated cell cycle is a hallmark of cancer. Mutations have been observed
in genes encoding CDKs, cyclins, CDK-activating enzymes, CDK substrates such as
Rb, and checkpoint proteins such as p53. In general, tumors that retain wild
type p53 have a better prognosis and a better response to therapy. p53 mutations
or mdm2 overexpression by amplification or other mechanisms occur at high
frequency in cancers. CDKs are considered the potential targets for anti-cancer
drugs. Some CDK inhibitors such as Seliciclib are undergoing clinical trials.
Seliciclib is being investigated for the treatment of non-small cell lung cancer
(NSCLC), leukemia, AIDS, and chronic inflammation disorders.
QIAGEN provides Cell Cycle, DNA Damage, Cytoskeleton Regulators, and
p53 Signaling Pathway PCR arrays to help analyze cell cycle control.
Complete Array List
