Page 71 - Concise Pathology for Exam Preparation ( PDFDrive )

56 SECTION I General Pathology

Phases of Cell Cycle

Interphase is supposedly a resting stage between cell divisions; however, it is actually a
period of several essential activities which are a prerequisite for making the next mitosis
possible, eg, synthesis of RNA and protein production. Interphase lasts about 12–24 hours
in mammalian tissue and can be divided into four phases: Gap 0 (G 0 ), Gap 1 (G 1 ),
S (synthesis phase) and Gap 2 (G 2 ). Human genome is doubled in the S phase, and halved
during M phase. The period between M and S phase is called G 1 ; and that between S and
M phases is called G 2 . So, the cell cycle consists of:
• G 0 (resting phase): When a cell leaves the cell cycle and quits dividing, it is said to be
in G 0 phase. This may be a transient phase or indefinite as in the case of a permanent
cell that has reached the end stage of its development and will not divide (eg, cardiac
myocytes or neurons).
• G 1 (presynthetic growth phase): In this phase, cells enlarge due to production of RNA
and synthesis of proteins. G 1 checkpoint is an important controlling mechanism that
ensures adequate preparation for DNA synthesis.
• S (synthetic phase): Synthesis of DNA and duplication of the centrosome takes place
in this phase.
• G 2 (premitotic growth phase): The cell continues to grow and produce new proteins like
G 1 phase. Another checkpoint (G 2 checkpoint) towards the end of G 2 phase determines
whether the cell is adequately prepared to proceed to the M phase and divide or not.
• M phase (mitotic phase): After protein synthesis and enlargement, the cell enters a
phase of division to give rise to two similar daughter cells. Mitosis lasts only 1–2 hours.
As in both G 1 and G 2 , the mitotic phase also has a checkpoint (called metaphase
checkpoint) that ensures the readiness of the cell to complete cell division.

Control of the Cell Cycle
Progression of the cell cycle is tightly regulated by the following proteins:
• Cyclins: These are classified as G1 cyclins (D cyclins), S-phase cyclins (cyclins E and A)
and mitotic cyclins (B cyclins). Their levels vary corresponding to the different phases of
cell cycle (cyclins are named so because of the cyclical nature of their production and
degradation during cell cycle).
• Cyclin-dependent kinases (CDKs): These cyclin-associated enzymes include a G 1
CDK (CDK4), an S-phase CDK (CDK2) and an M-phase CDK (CDK1). Their cellular
levels are relatively stable and they get activated on binding to the appropriate cyclin.

Steps in the Cell Cycle

1. The binding of G 1 -cyclins to CDKs is an indication to the cell to initiate chromosomal
replication. CDKs activated by combining with cyclins initiate the cell cycle by phos-
phorylating proteins such as retinoblastoma (RB) susceptibility protein, which
normally prevents cells from replicating by forming a tight, inactive complex with the
transcription factor E2F. Phosphorylation releases RB which activates E2F, which in
turn stimulates transcription.
2. The cyclin–CDK complexes are tightly regulated by CDK inhibitors (CDKIs), which
themselves are inhibited by other growth factors. CDKIs include several families. One
family comprised of p21 (CDKN1A), p27 (CDKN1B) and p57 (CDKN1C) inhibits
multiple CDKs. Another family comprised of p15 (CDKN2B), p16 (CDKN2A), p18
(CDKN2C) and p19 (CDKN2D) has selective effects on cyclins CDK4 and CDK6.
3. The G 1 /S checkpoint ensures the integrity of DNA before replication; whereas, the G 2 /M
checkpoint does the same after replication. These checkpoints monitor whether the cell
is prepared enough to enter mitosis. When there is DNA damage, the activation of
checkpoints delays the cell cycle and triggers DNA repair mechanisms. If DNA damage
is too severe to be repaired, the cells are eliminated by apoptosis.

mebooksfree.com