chapter 26
Regulation of Gene Expression
located at some distance upstream or downstream from
the promoter.
Steroid receptor proteins are synthesized from a gene
family that shows a high degree of homology in the DNA
binding region. All steroid receptors belong to one of five
classes: androgen receptor (AR), estrogen receptor (ER),
glucocorticoid receptor (GR), mineralocorticoid receptor
(MR), and progesterone receptor (PR). Also, all receptors
contain a zinc finger motif which, if altered by mutation,
destroys the steroid receptor’s function.
G-Protein Diseases
Mutations that alter the functions of trimeric
nucleotide-binding proteins (G-proteins)
are responsi-
ble for wide range of diseases (Table 26-5). While most
of these diseases are quite rare, the identification of
an altered G-protein in hypertension is estimated to af-
fect as many as
15% of patients with hypertension.
G-proteins relay signals from hormones, neurotransmit-
ters, and other extracellular agents to different intracel-
lular effectors that regulate enzymes and ion channels.
G-proteins are responsible for signal transfer from more
than 1000 cell receptors. Changes in G-proteins cause ex-
cessive or insufficient transmission of signals that are es-
sential for proper cellular functioning.
G-proteins consist of three subunits: an
subunit that
is loosely bound to a dimer consisting of a
subunit that
is tightly bound to a
subunit. Human chromosomes con-
tain genes for 16a, 6/1, and 12
subunits. Thus, a large
TA BLE 26-5
Diseases Caused by Mutations That Alter
the Signal Activities of G Proteins
Excess Signal
Pituitary and thyroid adenomas
Adrenal and ovarian adenomas
McCune-Albright syndrome
Deficient Signal
Pseudohypoparathyroidism type la
Deficient or Excessive Signal
Essential hypertension
variety of Ga proteins define different G-protein trimers
that regulate signaling pathways such as cAMP synthesis,
cGMP breakdown, closing of Ca2+ channels, and opening
of K+ channels.
The activity of G-proteins is regulated by the binding
and hydrolysis of guanosine triphosphate (GTP) by the
Ga subunit. If guanosine diphosphate (GDP) is bound
to the
subunit, it will associate with the
f y
but the trimer is inactive. When a cell receptor is activated,
the trimer releases GDP and the a subunit is able to bind
GTP. After binding GTP the
subunit dissociates from
subunit and from the receptor. Either the a-GTP
complex or the
f y
subunits can then activate downstream
effectors. Thus, defects in any of the numerous G-proteins
may alter cellular biochemistry and cause disease.
Regulation of Transcription by Methylation
Most cells contain several enzymes that transfer a methyl
group from S-adenosylmethionine (Chapter 17) to cyto-
sine or adenine in DNA. These
DNA methylases
are both
base-specific and sequence-specific. Another enzyme that
methylates cytosine only in particular CpG sequences also
is important for transcription. In a few cases, particularly in
vertebrates, methylation of CpG sequences prevents tran-
scription of some genes.
Evidence for a regulatory role of methylation is:
1. Certain genes are heavily methylated in cells in which
the gene is not expressed and unmethylated in cells in
which the gene is expressed.
In vitro
methylation of the upstream site of a cloned
y-globulin gene prevents transcription. Methylation
outside the upstream sequence does not inhibit
3. If the base analogue 5-azacytidine is added to cultures
of growing cells, newly made DNA contains the
analogue, and methylation of CpG sites containing
the analogue fails to take place (5-azacytidine is also
a general inhibitor of many methylases). Cells in such
cultures gain the ability to make proteins whose
synthesis is normally turned off (i.e., in cells growing
in medium lacking the base analogue).
4. The housekeeping genes, which provide for general
cell function and which are continuously transcribed,
are rarely methylated in or near their initiation
Undifferentiated and precursor cells often replicate. If
methylation actually prevents gene expression in some
types of cell, an inhibitory methylated site must be inher-
ited as a methylated site in a daughter strand during DNA
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