2. Cell Cycle
• A series of events that leads to the duplication and division of a cell
• The components that regulate cell growth and division also play key roles
in the cessation of cell division that is required for cells to differentiate
• Control of the cell cycle is of major importance to human health because
cancer is usually caused by perturbations of cell-cycle regulation.
• Stratified epithelium that forms skin illustrate the most common types of
cell
• The basal layer of the epithelium is composed of stem cells that divide only
occasionally
4. Principles of Cell-Cycle Regulation
• The goal of the cell cycle in is to produce two daughter cells that are
accurate copies of the parent
• The chromosome cycle is driven by a sequence of enzymatic cascades
• Progress through the cell cycle is irreversible because each new state
arises by destruction or inactivation of key activities characteristic of
the preceding state
6. Phases of the Cell Cycle
• Recognition of these phases began in 1882, when Flemming named the
process of nuclear division mitosis
• Once DNA was recognized as the agent of heredity in the 1940s, it was
deduced that it must be duplicated at some time during interphase
• In 1953, a key experiment identified the four cell-cycle phases as they are
known today
• The chromosomal DNA is replicated during S phase (synthetic phase).
7. G1 Phase
• G1 is typically the longest and most variable cell-cycle phase
• When cells are “born” they are roughly half the size they were before
mitosis, and during G1, they grow back toward an optimal size
• Many activities involved in cell-cycle progression are repressed
• Cancer cells often have defects in restriction point control
8.
9. G0 and Growth Control
• Most cells of multicellular organisms differentiate to carry out
specialized functions and no longer divide
• Cells often enter G0 directly as they exit their last mitosis
• G0 cells are not dormant and is not necessarily permanent
• Cell-cycle re-entry involves changes in gene expression, it is highly
regulated
10. S Phase
• The DNA must be initiated at many different sites, termed origins of
replication, each origin fires only once per cell cycle
• The cyclic nature is driven by fluctuations in the activity of cyclin-
dependent kinases and protein destruction machinery
• During replication, the duplicated DNA molecules, called sister
chromatids, become linked to each other by a protein complex called
cohesin
11.
12. G2 Phase
• G2 is a relatively brief period during which key enzymatic activities
that will trigger the entry into mitosis
• Along the way, the chromatin and cytoskeleton are prepared for the
dramatic structural changes that will occur during mitosis
• If damaged DNA is detected during G2, a checkpoint activates the
DNA damage response and delays entry of the cell into mitosis
13.
14. M Phase
• Chromosomes and cytoplasm are partitioned into two daughter cells
• Mitosis is normally divided into five discrete phases.
• Prophase is defined by the onset of chromosome condensation and is
actually the final part of G2 phase.
• The duplicated centrosomes separate and form the two poles of the
mitotic spindle.
• Prometaphase begins when the nuclear envelope breaks down and
chromosomes begin to attach randomly to microtubules
• When all chromosomes are properly attached, the cell is said to be in
metaphase
15. M Phase
• The exit from mitosis begins at anaphase with abrupt separation of the two
sister chromatids.
• The separated sister chromatids move to the two spindle poles (anaphase
A), which themselves move apart (anaphase B).
• The nuclear envelope reforms on the surface of the chromatin. At this
point, the cell is said to be in telophase
• Finally, during telophase, a contractile ring of actin and myosin assembles
as a circumferential belt at the cortex midway between spindle poles and
constricts the equator of the cell.
Like stem cells, fibroblasts of the connective tissue (see Fig. 28.2) typically are in a nondividing state, but they can be stimulated to enter the cell cycle following wounding or other stimuli
In the most extreme case, the nervous system contains a few stem cells and a few dividing glial cells, but most neurons, once differentiated, can live for more than 100 years without dividing again.
Control networks and checkpoints regulate progression of the cell cycle
Checkpoints are biochemical circuits that detect external or internal stimuli and send appropriate signals to the cell-cycle system
Cells must receive appropriate growth stimuli from their environment to progress past this point in the G1 phase
DNA damage checkpoints operate throughout interphase. If damage is detected, the DNA damage response initiates a cascade of events that blocks cellcycle progression and can also trigger cell death by apoptosis.
These sensors activate transducers, which include both protein kinases and transcriptional activators
The G1 phase (first gap phase) is the interval between mitosis and the start of DNA replication
The G2 phase (second gap phase) is the interval between the completion of DNA replication and mitosis
The G1 and G2 phases vary in length and are very short in some early embryos
If the supply of nutrients is poor or if cells receive an antiproliferative stimulus such as a signal to embark on terminal differentiation, they delay their progress through the cell cycle in G1 or exit the cycle to enter G0
However, if appropriate positive stimuli are received, cells overcome the restriction point block and trigger a program of gene expression that commits them to a new cycle of DNA replication and cell division
At least two mechanisms slow or stop the cell cycle by inactivating Cdks
During G2 phase, the protein kinases Myt1 and Wee1 hold Cdk1 in check by phosphorylation
the regulatory kinases only following cyclin binding, so this phosphorylation of Cdks depends, at least in part, on the availability of cyclins
Cdc25A regulates both the G1 → S and G2 → M transitions and is essential for life of the cell
A parallel mechanism for inactivating Cdks involves proteins called the cyclin-dependent kinase inhibitors (CKIs) and inhibitors of Cdk4 (INK4)
