Microbiology and Immunology

Cell cycle (eukaryotic), genetic regulation of WORLD OF MICROBIOLOGY AND IMMUNOLOGY

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CELL CYCLE(EUKARYOTIC), GENETIC

REGULATION OFCell cycle (eukaryotic), genetic regulation of

Although prokaryotes (i.e., non-nucleated unicellular organ-

isms) divide through binary fission, eukaryotesundergo a

more complex process of cell division because DNAis packed

in several chromosomeslocated inside a cell nucleus. In

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 con-

trols are lost or inhibited, abnormal overgrowth will occur and

may lead to impairment of function and disease.

Cells are mainly induced into proliferation by growth fac-

tors or hormones that occupy specific receptors on the surface

of the cell membrane, and are also known as extra-cellular lig-

ands. 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 by

hormones. PDGF and FGF act by regulating the phase G2 of the

cell cycle and during mitosis. After mitosis, they act again stim-

ulating the daughter cells to grow, thus leading them from G0 to

G1. Therefore, FGF and PDGF are also termed competence fac-

tors, 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, thy-

rotrophic hormone, one of the hormones produced by the pitu-

itary gland, induces the proliferation of thyroid gland’s cells.

Another pituitary hormone, known as growth hormone or soma-

totrophic hormone (STH), is responsible by body growth during

childhood and early adolescence, inducing the lengthening of

the long bones and protein 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 sig-

naling pathway, as well as along the apoptotic pathways, several

gene products (proteins and enzymes) are involved in an

orderly sequence of activation and inactivation, forming com-

plex webs of signal transmission and signal amplification 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 accomplish 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 transition 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-

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