section 26.4
Mechanisms of Gene Regulation
F I G U R E 2 6 - 1 0
gene. Two distinct TATA sequences lead to production of different primary transcripts, which contain
the same coding sequences. Two modes of intron excision lead to the formation of distinct mRNA molecules that encode
proteins having different amino terminal regions and the same carboxy terminal regions.
conditions that are classified as
multiple endocrine neo-
Alternative RNA Splicing and Editing
M ost primary transcripts in eukaryotic cells derive from
com plete rem oval o f all introns and com plete joining o f all
exons. This results in on ly on e sp ecies o f mature m R N A
being synthesized from each primary transcript. However,
m any eukaryotic genes can give rise to m any different
form s o f mature m R N A s using different prom oters and
different polyadenylation sites (discussed above), as w ell
as by
alternative splicing.
This form o f regulation o f R N A
processing is especially useful because a sin gle gene can be
expressed differently at various developm ental stages or in
different tissues o f the sam e organism . O ne exam ple is the
troponin T
gene that synthesizes the fast skeletal m uscle
protein. This gene consists o f 18 exons; however, only 11
are found in all mature m R N A s. Five o f the exons can
be included or excluded and tw o are m utually exclusive;
if one is included, the other is excluded. A ltogether, 64
different mature m R N A s can be produced by alternative
splicing o f the primary transcript o f the troponin T gene.
RNA editing
involves processing o f R N A in the nucleus
by en zym es that change a single nucleotide (insertion,
deletion, or substitution). O ne exam ple is
tein B
(apo B ) gene. In the liver this gene produces a
4536-am ino-acid protein (apo B 100), w hereas in the
sm all intestine the sam e gene produces a 2152-am ino-acid
protein (apo B 48). The truncated protein is identical in
am ino acid sequence to the first 2 152 am ino acids in apo
B 100. This occurs because in cells o f the sm all intestine
one nucleotide (at position 6666) is edited by deam ination
o f a cytosine residue. The conversion o f a cytosine
to uracil at this position produces a stop codon that
term inates translation and produces the truncated protein.
Thus, selective editing o f m R N A s prior to translation in
specific tissues is used to produce different proteins.
Regulation of Iron Utilization in Cells
Iron is an im portant constituent o f hum an cells and reg-
ulates m any b iochem ical functions (Chapter 29). Iron
acts as an effector m olecule in the translation o f several
m R N A s by binding to either 3' or 5' stem -loop structures,
iron-response the elements
(IREs), that flank the
coding sequences for several gen es w h ose expression is
regulated by iron. In particular, the inR N A s for the trans-
ferrin receptor, light and heavy chains o f ferritin, an ery-
throlytic form o f am inolevulinic acid synthetase, and a
form o f m itochondrial aconitase are regulated by IREs
and an
IRE-binding protein
(IR E-BP). The IRE in the
ferritin in R N A is in the 5' flanking sequence. Translation
o f the m R N A is regulated by binding o f IR E-BP w hose
activity, in turn, is regulated by the concentration o f iron
in the cell. In contrast, the IRE o f transferrin m R N A is in
the 3' flanking sequence; binding o f IR E -B P to this IRE
regulates turnover o f the m R N A . This exam ple illustrates
the variety o f w ays that gene expression can be regulated
under varying p hysiological conditions in hum an cells.
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