Page 224 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 17

CONTROL OF CELL DIVISION

Martin Fischer, Chi V. Dang, and James A. DeCaprio

THE CELL DIVISION CYCLE mitogens), cells arrest in G 1, and those that are already in S, G 2, or
M phase usually complete the round to which they have been com-
The mammalian cell cycle is divided into four phases: mitosis (M), mitted and arrest only when they reach G 1 again. For example, when
DNA synthesis (S), and the gap phases G 1 and G 2 (Fig. 17.1). Mitosis the 40S ribosomal protein S6 is missing, cells stop proliferation. If
is recognized when cells visibly undergo cell division and chromatin cell size or mass were not regulated, S phase entry might cause cells
becomes condensed, sequentially progressing through prophase, to become progressively smaller or be at risk for DNA replication
metaphase, anaphase, and telophase. The G 1 phase occurs immedi- errors as a result of insufficient substrates. Cell size regulation is
ately after mitosis has been completed and ends when DNA synthesis intimately linked to ribosome biogenesis and nutrient-sensing
begins. During S phase, cells duplicate their entire genome by DNA systems, central to which are the phosphoinositide 3-kinase (PI3K)
replication. G 2 occurs after DNA synthesis has been completed and and target of rapamycin (TOR) pathways. Notably, when the MYC
before chromosomal condensation in mitosis. Although the duration transcription factor is missing, cells slow their growth and often do
of the S, G 2 , and M phases is relatively constant for most mammalian not enter S phase. MYC regulates cyclin and cyclin-dependent kinase
cells, there can be a large degree of variability in the duration of G 1 . (CDK) genes as well as genes involved in ribosome biogenesis and
1
Among the earliest observations regarding the generation time for translation. In aggregate, studies of a variety of cell systems indicate
cells, it was shown that by varying the growth conditions, the length that cell size regulation is linked to cell proliferation, except in special-
of a cell division cycle could change, with the length of G 1 responsible ized cells that undergo endoreplication or in embryos shortly after
for most of this variability. Although cells progress through S, G 2 , fertilization, when G 1 is virtually undetectable, and there is no cell
and M phases in relatively invariable time periods, the length of the enlargement. As a result, the original mass of egg cytoplasm is parti-
G 1 phase is highly variable, and this variability is dependent at least tioned among thousands of cells within a few hours without a
in part on the presence of growth factors. noticeable increase in size.

Quiescence and Differentiation S Phase

Quiescence (G 0 ) is a nonproliferative state in which viable cells have S phase is the period of wholesale DNA synthesis during which the
left the cell cycle and may remain for prolonged periods. Quiescent cell replicates its genetic content; a normal diploid somatic cell with
cells may be difficult to distinguish morphologically from cells in a a 2N complement of DNA at the beginning of S phase acquires a
prolonged G 1 phase, but they can be distinguished by different 4N complement of DNA at its end. (Recall that N = 1 copy of each
markers. Terminally differentiated cells, such as neutrophilic granu- chromosome per cell [haploid]; 2N = 2 copies [diploid].) The dura-
locytes, muscle cells, and neurons, have irreversibly exited the cell tion of S phase may vary from only a few minutes in rapidly dividing,
cycle during the process of differentiation and are examples of cells early embryo cells to a few hours in most somatic cells. Early embryo
that have irreversibly entered G 0 . Other cells, including stem cells, cells generally “live off” the accumulated stores of maternal RNA and
reversibly enter G 0 and may be induced to reenter the cell cycle with proteins present in the egg and are transcriptionally silent, whereas
appropriate stimuli, such as growth factors. Differentiation provides cells in later development and mature organisms must actively tran-
the organism with a supply of cells to execute specific and specialized scribe subsets of their genes to survive and maintain specialized
functions. In some cell types, such as muscle and nerve cells, differ- functions. The longer time required for the latter to complete S phase
entiation and proliferation are mutually exclusive fates, and cells probably allows these cells to coordinate DNA replication with
undergo “terminal differentiation.” In other cell types, such as those transcription and to preserve higher-order gene and chromatin
of the hematopoietic lineage, proliferation may continue after cells structural information that influences gene expression for transmis-
acquire differentiated characteristics. For example, erythroblasts, sion to progeny cells.
myeloblasts, and megakaryoblasts are committed to particular dif-
ferentiation pathways and possess lineage-specific markers yet con-
tinue to proliferate. T and B lymphocytes are fully differentiated and G 2 Phase
express antigen-specific receptors but can be induced to proliferate
when appropriately stimulated. G 2 is the period or gap between S and M phases when cells have
finished replicating their DNA, are preparing to divide, and have a
4N DNA content. For most cells entering S phase, passage through
G 1 Phase G 2 is “automatic,” and the duration of G 2 is fixed, except under
unusual circumstances. For example, G 2 duration can be extremely
G 1, which occupies the period or gap between M and S phases, is the short and is essentially undetectable in rapidly proliferating, early
interval between the completion of one round of cell division and embryonic cells.
initiation of the next. Its duration is the most variable, can be pro-
longed depending on the cell type, and is subject to regulation by
environmental factors such as the availability of growth factors and M Phase
nutrients. It is the period of cell growth, and as a first approximation,
the amount of time a cell spends in G 1 is inversely related to its rate Mitosis, or M phase, is the period of actual nuclear and cell division
of proliferation. A certain increase in mass usually is required before during which the duplicated chromosomes are divided equally
the cell initiates the next S phase. When conditions are unsuitable between two progeny cells. It is obvious microscopically as the period
for proliferation (e.g., because of insufficient nutrients or absence of of chromosome condensation and segregation, nuclear division

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