section 26.4

Mechanisms of Gene Regulation

in

Eukaryotes

607

F I G U R E 2 6 - 1 0

Chicken

LC1/LC3

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-

plasias.

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

apolipopro-

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,

called

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.