WORLD OF MICROBIOLOGY AND IMMUNOLOGY Genetic regulation of eukaryotic cells243•
eukaryotes, cell division may take two different paths, in
accordance with the cell type involved. Mitosis is a cellular
division resulting in two identical nuclei is performed by
somatic cells. The process of meiosis results in four nuclei,
each containing half of the original number of chromosomes.
Sex cells or gametes (ovum and spermatozoids) divide by
meiosis. Both prokaryotes and eukaryotes undergo a final
process, known as cytoplasmatic division, which divides the
parental cell into new daughter cells.
The series of stages that a cell undergoes while pro-
gressing to division is known as cell cycle. Cells undergoing
division are also termed competent cells. When a cell is not
progressing to mitosis, it remains in phase G0 (G zero).
Therefore, the cell cycle is divided into two major phases:
interphase and mitosis. Interphase includes the phases (or
stages) G1, S and G2, whereas mitosis is subdivided into
prophase, metaphase, anaphase and telophase.
The cell cycle starts in G1, with the active synthesis of
RNAand proteins, which are necessary for young cells to grow
and mature. The time G1 lasts, varies greatly among eukary-
otic cells of different species and from one tissue to another in
the same organism. Tissues that require fast cellular renova-
tion, such as mucosa and endometrial epithelia, have shorter
G1 periods than those tissues that do not require frequent ren-
ovation or repair, such as muscles or connective tissues.
The cell cycle is highly regulated by several enzymes,
proteins, and cytokinesin each of its phases, in order to ensure
that the resulting daughter cells receive the appropriate
amount of genetic information originally present in the
parental cell. In the case of somatic cells, each of the two
daughter cells must contain an exact copy of the original
genome present in the parental cell. Cell cycle controls also
regulate when and to what extent the cells of a given tissue
must proliferate, in order to avoid abnormal cell proliferation
that could lead to dysplasia or tumor development. Therefore,
when one or more of such controls are lost or inhibited, abnor-
mal overgrowth will occur and may lead to impairment of
function and disease.
Cells are mainly induced into proliferation by growth
factors or hormones that occupy specific receptors on the sur-
face of the cell membrane, and are also known as extra-cellu-
lar ligands. Examples of growth factors are as such: epidermal
growth factor (EGF), fibroblastic growth factor (FGF),
platelet-derived growth factor (PDGF), insulin-like growth
factor (IGF), or hormones. PDGF and FGF act by regulating
the phase G2 of the cell cycle and during mitosis. After mito-
sis, they act again stimulating the daughter cells to grow, thus
leading them from G0 to G1. Therefore, FGF and PDGF are
also termed competence factors, whereas EGF and IGF are
termed progression factors, because they keep the process of
cellular progression to mitosis going on. Growth factors are
also classified (along with other molecules that promote the
cell cycle) as pro-mitotic signals. Hormones are also pro-
mitotic signals. For example, thyrotrophic hormone, one of the
hormones produced by the pituitary gland, induces the prolif-
eration of thyroid gland’s cells. Another pituitary hormone,
known as growth hormone or somatotrophic hormone (STH),
is responsible by body growth during childhood and early ado-lescence, inducing the lengthening of the long bones and pro-
tein synthesis. Estrogens are hormones that do not occupy a
membrane receptor, but instead, penetrate the cell and the
nucleus, binding directly to specific sites in the DNA, thus
inducing the cell cycle.
Anti-mitotic signals may have several different origins,
such as cell-to-cell adhesion, factors of adhesion to the extra-
cellular matrix, or soluble factor such as TGF beta (tumor
growth factor beta), which inhibits abnormal cell proliferation,
proteins p53, p16, p21, APC, pRb, etc. These molecules are
the products of a class of genes called tumor suppressor genes.
Oncogenes, until recently also known as proto-oncogenes,
synthesize proteins that enhance the stimuli started by growth
factors, amplifying the mitotic signal to the nucleus, and/or
promoting the accomplishment of a necessary step of the cell
cycle. When each phase of the cell cycle is completed, the pro-
teins involved in that phase are degraded, so that once the next
phase starts, the cell is unable to go back to the previous one.
Next to the end of phase G1, the cycle is paused by tumor sup-
pressor geneproducts, to allow verification and repair of
DNA damage. When DNA damage is not repairable, these
genes stimulate other intra-cellular pathways that induce the
cell into suicide or apoptosis (also known as programmed cell
death). To the end of phase G2, before the transition to mito-
sis, the cycle is paused again for a new verification and deci-
sion, either mitosis or apoptosis.
Along each pro-mitotic and anti-mitotic intra-cellular
signaling pathway, as well as along the apoptotic pathways,
several gene products (proteins and enzymes) are involved
in an orderly sequence of activation and inactivation, form-
ing complex webs of signal transmission and signal amplifi-
cation to the nucleus. The general goal of such cascades of
signals is to achieve the orderly progression of each phase of
the cell cycle.
Interphase is a phase of cell growth and metabolic activ-
ity, without cell nuclear division, comprised of several stages
or phases. During Gap 1 or G1, the cell resumes protein and
RNA synthesis, which was interrupted during mitosis, thus
allowing the growth and maturation of young cells to accom-
plish their physiologic function. Immediately following is a
variable length pause for DNA checking and repair before cell
cycle transition to phase S during which there is synthesis or
semi-conservative replication or synthesis of DNA. During
Gap 2 or G2, there is increased RNA and protein synthesis,
followed by a second pause for proofreading and eventual
repairs in the newly synthesized DNA sequences before tran-
sition to mitosis.
At the start of mitosis, the chromosomes are already
duplicated, with the sister-chromatids (identical chromo-
somes) clearly visible under a light microscope. Mitosis is
subdivided into prophase, metaphase, anaphase, and
telophase.
During prophase there is a high condensation of chro-
matids, with the beginning of nucleolus disorganization and
nuclear membrane disintegration, followed by the start of cen-
trioles’ migration to opposite cell poles. During metaphase the
chromosomes organize at the equator of a spindle apparatus
(microtubules), forming a structure termed metaphase plate.womi_G 5/6/03 3:18 PM Page 243