CELL CYCLE AND ITS REGULATION
The simplest type of reproduction entails the division of a “parent” cell into two “daughter” cells.
This occurs as part of the cell cycle, a series of events that prepares a cell to divide followed by
the actual division process, called mitosis. The eukaryotic cell cycle commonly is represented as
four stages. The chromosomes and the DNA they carry are copied during the S (synthesis)
phase. The replicated chromosomes separate during the M (mitotic) phase, with each daughter
cell getting a copy of each chromosome during cell division. The M and S phases are separated
by two gap stages, the G1 phase and G2 phase, during which mRNAs and proteins are made. In
single-celled organisms, both daughter cells often (though not always) resemble the parent cell.
In multicellular organisms, stem cells can give rise to two different cells, one that resembles the
parent cell and one that does not. Such asymmetric cell division is critical to the generation of
different cell types in the body. During growth the cell cycle operates continuously, with newly
formed daughter cells immediately embarking on their own path to mitosis. Under optimal
conditions bacteria can divide to form two daughter cells once every 30 minutes. At this rate, in
an hour one cell becomes four; in a day one cell becomes more than 1014, which if dried would
weigh about 25 grams. Under normal circumstances, however, growth cannot continue at this
rate because the food supply becomes limiting. Most eukaryotic cells take considerably longer
than bacterial cells to grow and divide. Moreover, the cell cycle in adult plants and animals
normally is highly regulated. This tight control prevents imbalanced, excessive growth of tissues
while assuring that worn-out or damaged cells are replaced and that additional cells are formed
in response to new circumstances or developmental needs. For instance, the proliferation of red
blood cells increases substantially when a person ascends to a higher altitude and needs more
capacity to capture oxygen. Some highly specialized cells in adult animals, such as nerve cells
and striated muscle cells, rarely divide, if at all. The fundamental defect in cancer is loss of the
ability
to control the growth and division of cells.
In a nutshell, the four stages of the cell cycle are;
Cell division in eukaryotes occurs in four well-defined stages. In the S (synthesis) phase, the
DNA is replicated to produce copies for both daughter cells.
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In the G2 phase (G indicates the gap between divisions), new proteins are synthesized
and the cell approximately doubles in size.
In the M phase (mitosis), the maternal nuclear envelope breaks down, matching
chromosomes are pulled to opposite poles of the cell.
Each set of daughter chromosomes is surrounded by a newly formed nuclear envelope,
and cytokinesis pinches the cell in half, producing two daughter cells.
In embryonic or rapidly proliferating tissue, each daughter cell divides again, but only
after a waiting period (G1).
In cultured animal cells the entire process takes about 24 hours. After passing through
mitosis and into G1, a cell either continues through another division or ceases to divide,
entering a quiescent phase (G0) that may last hours, days, or the lifetime of the cell.
When a cell in G0 begins to divide again, it reenters the division cycle through the G1
phase.
Differentiated cells such as hepatocytes or adipocytes have acquired their specialized
function and form; they remain in the G0 phase.
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The Eukaryotic cell cycle
The regulation of the cell division by cyclin-dependent protein kinases (CDKs) through
phosphorylation of critical proteins;
The structure of the nuclear envelope is maintained in part by highly organized mesh
works of intermediate filaments composed of the protein laminin.
Breakdown of the nuclear envelope before segregation of the sister chromatids in
mitosis is partly due to the phosphorylation of laminin by a CDK, which causes
laminin filaments to depolymerize.
A second kinase target is the ATP-driven actin myosin contractile machinery that
pinches a dividing cell into two equal parts during cytokinesis.
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After the division, CDK phosphorylates a small regulatory subunit of myosin, causing
dissociation of myosin from actin filaments and inactivating the contractile
machinery.
Subsequent dephosphorylation allows reassembly of the contractile apparatus for the
next round of cytokinesis.
A third and very important CDK substrate is the retinoblastoma protein, pRb; when
DNA damage is detected, this protein participates in a mechanism that arrests cell
division in G1.
Named for the retinal tumor cell line in which it was discovered, pRb functions in
most, perhaps all, cell types to regulate cell division in response to a variety of
stimuli.
Unphosphorylated pRb binds the transcription factor E2F; while bound to pRb, E2F
cannot promote transcription of a group of genes necessary for DNA synthesis (the
genes for DNA polymerase α, ribonucleotide reductase, and other proteins).
In this state, the cell cycle cannot proceed from the G1 to the S phase, the step that
commits a cell to mitosis and cell division.
The pRb-E2F blocking mechanism is relieved when pRb is phosphorylated by cyclin
E–CDK2, which occurs in response to a signal for cell division to proceed.
When the protein kinases ATM and ATR detect damage to DNA, such as a single-
strand break, they activate p53 to serve as a transcription factor that stimulates the
synthesis of the protein p21.
This protein inhibits the protein kinase activity of cyclin E–CDK2.
In the presence of p21, pRb remains unphosphorylated and bound to E2F, blocking
the activity of this transcription factor, and the cell cycle is arrested in G1.
This gives the cell time to repair its DNA before entering the S phase, thereby
avoiding the potentially disastrous transfer of a defective genome to one or both
daughter cells.
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Regulation of passage from G1 to S by phosphorylation of pRb
