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chapter 26
Regulation of Gene Expression
However, synthesis of mRNA in eukaryotes is not a simple
matter of initiation at a promoter, as it is in prokaryotes,
but includes several steps in which the primary transcript
is converted to mRNA (Chapter 25). Control of these pro-
cessing steps is also used to regulate gene expression in
eukaryotes.
A variety of differences between the regulatory mech-
anisms of prokaryotes and eukaryotes are evident. First,
transcription of related genes is initiated in response to
a single signal. Second, a single polygenic primary tran-
script may be differentially processed to yield a set of dis-
tinct mRNA molecules each encoding one protein. Third,
large proteins can be processed into small, active polypep-
tides. The second and third mechanisms are unique to eu-
karyotes.
Housekeeping Genes and RNases
Many proteins in eukaryotic cells such as those involved
in glycolysis (Chapter 13) are needed continuously; the
genes encoding such proteins are called
housekeeping
genes.
A variety of regulatory mechanisms have evolved
to ensure a constant supply of these gene products. In some
instances the amount of each protein may be regulated by
the strength of the promoter and ribosomal binding site.
However, in housekeeping genes with strong promoters,
the gene product functions as a repressor and binds to a
site adjacent to the gene, thus regulating the level of tran-
scription. This mechanism is called
autoregulation.
If the
gene product is in short supply, transcription is activated;
as the concentration of the product increases, the level of
transcription is reduced.
In bacteria, mRNAs are rapidly degraded, which is es-
sential for an organism that must adapt to rapidly changing
environments. The RNase E protein (product of the
rne
gene) is essential in controlling the stability of mRNAs in
E. coli.
The RNase E mRNA, in turn, is autoregulated; an
amino terminal fragment of RNase E acts as a repressor
of the
rne
gene. In human cells an analogous RNase ac-
tivity has been purified using antibodies against RNase E
and both RNases recognize the same sequence (AUUUA).
At least four RNase families can be identified in eukary-
otes that have significant homology to pancreatic RNases.
Overall, it is estimated that there should be as least 100
different eukaryotic RNases. Because of the crucial roles
RNases and their structural homologues play in regula-
tion of gene expression, splicing of primary transcripts,
organogenesis, and other cellular activities, RNases are
often referred to as housekeeping enzymes.
RNase activity in serum and cell extracts is elevated in
a variety of cancers and infectious diseases. The level of
RNases is regulated by both activators and inhibitors. The
TA BLE 26-2
Diseases Associated with Elevated Levels o f RNase
Activity in Body Fluids or Cell Extracts
Disease
RNase
Colorectal adenocaricnoma
RNase L
CML monocytes
RNase L
Chronic fatigue syndrome
RNase L
Liver diseases
poly-C degrading RNase
Chronic myeloid leukemia
> 2 0 0
folds increase in
(CML)
endoribonuclease activity
Pancreatic necrosis
pancreatic RNase
Neurological infectious
diseases
poly-C degrading RNase
cellular content of RNase depends on both regulation of
endogenous synthesis as well as the uptake of enzymes
synthesized in the pancreas. Because of the multiple reg-
ulatory roles of RNases in cells, elevated levels are as-
sociated with a wide spectrum of diseases (Table 26-2)
and serve as useful markers in diagnosis. RNases also are
being investigated for antifungal, antiviral, and antitumor
activity, and drugs are being developed that are based on
specific RNase activities.
Gene Families
Eukaryotic genes are not arranged in operons, since each
mRNA contains only one gene. However, many systems
are grouped into gene families either because of their loca-
tion or, more commonly, because of their related function.
For example, the set of tRNA genes, whose transcription
is correlated by some unknown mechanism, is an example
of a gene family. Another example, whose regulation is
particularly simple, is the family of rRNA genes. Eukary-
otic ribosomes contain one copy each of 5S, 5.8S, 18S, and
28S rRNA, and these are synthesized in equal numbers.
The 5.8S, 18S, and 28S rRNA molecules are components
of a single transcript that is cleaved to yield one copy of
each molecule. The 5S rRNA is, however, part of another
transcript. How the ratio of the 5S rRNA to the others is
maintained is not known; possibly, the promoter strengths
of the two transcripts are the same. However, this kind of
gene organization is not particularly common, and related
genes often reside on different chromosomes.
Of particular interest are the developmentally regulated
gene families. Similar, but not identical, proteins having
the same properties are made at different stages of develop-
ment. A well-studied example is
hemoglobin,
a tetrameric
protein containing two
a
subunits and two
p
subunits.
