An Analysis of Vertebrate mRNA Sequences: Intimations of Translational Control

Abstract

Five structural features in mRNAs have been found to contribute to the fidelity and efficiency of initiation by eukaryotic ribosomes. Scrutiny of vertebrate cDNA sequences in light of these criteria reveals a set of transcripts--encoding oncoproteins, growth factors, transcription factors, and other regulatory proteins--that seem designed to be translated poorly. Thus, throttling at the level of translation may be a critical component of gene regulation in vertebrates. An alternative interpretation is that some (perhaps many) cDNAs with encumbered 5' noncoding sequences represent mRNA precursors, which would imply extensive regulation at a posttranscriptional step that precedes translation.

Full text

Mini-Review
An
Analysis
of
Vertebrate
mRNA
Sequences
:
Intimations
of
Translational
Control
Marilyn
Kozak
Department
of
Biochemistry, University
of
Medicine
and
Dentistry
of
New
Jersey,
Piscataway,
NJ
08854
Abstract
.
Five
structural features
in
mRNAs
have
been
found
to
contribute
to
the
fidelity
and
efficiency
of
initiation
by
eukaryotic
ribosomes
.
Scrutiny
of
vertebrate
cDNA
sequences
in
light
of
these
criteria
reveals
a
set
of
transcripts-encoding
oncoproteins,
growth
factors,
transcription
factors,
and
other
regu-
latory
proteins-that
seem
designed
to
be
translated
poorly
.
Thus,
throttling at
the
level
of
translation
may
be
a
critical
component
of gene
regulation
in
vertebrates
.
An
alternative
interpretation
is
that
some
(perhaps
many)
cDNAs
with
encumbered
5'
noncod-
ing
sequences
represent
mRNA
precursors,
which
would
imply
extensive regulation
at a
posttranscrip-
tional
step
that
precedes
translation
.
NITIATIO
N
of
translation
in
multicellular
eukaryotes
is
in-
fluenced
by
five
aspects of
mRNA
structure
:
(a)
the
m7G
cap
(355)
;
(b)
the
primary
sequence or
context
surround
ing the
AUG
codon
(187,
190,
194)
;
(c)
the
position
of the
AUG
codon,
i
.e
.,
whether
it
is
the
first
AUG
in
the
message
(186)
;
(d)
leader
length
(198,
199)
;
and
(e)
secondary
struc-
ture
both
upstream
(188,
195)
and
downstream
(196)
from
the
AUG
codon
.
Elsewhere
(200)
I
have
reviewed
the
evi-
dence
for
these
five
features
and
explained
how
they
work
together
to
determine
the
fidelity
and
efficiency
of
initiation
.
A
scanning
mechanism
for
initiation
can
explain
many
of the
effects
of
cap,
context,
position,
etc
.
The
scanning
model
(193) in
its
simplest
form
postulates
that
a
40S
ribosomal
subunit,
carrying
Met-tRNA
;^"
and
an
imperfectly
defined
set
of
initiation
factors
(302), enters
at
the
5'
end
of the
mRNA
and
migrates
linearly
until
it
reaches
the
first
AUG
codon,
whereupon
a
60S
subunit
joins
and
the
first
peptide
bond
is
formed
.
Evidence
in
support
of the
model
has
been
adduced
previously
(62,
193,
197)
.
More
recent
evidence
for
scanning
includes the
apparent
queuing
of
40S
ribosomal
subunits
on
long
leader
sequences
(199)
and
the
stalling
of
40S
subunits
on
the
5'
side
of a
stable
hairpin
structure
intro-
duced
between
the
cap and
the
AUG
codon
(195)
.
The
possi-
bility
of
initiation
by
a
mechanism
other
than
scanning
has
been
proposed
(158)
and
is
evaluated
elsewhere
(197)
.
The
trick
to
identifying
elements
in
5'
noncoding
se-
quences
that
can
modulate
translation
was
to
isolate
each
feature
(200),
an
approach
made
possible
by
the
techniques
ofgenetic
engineering
.
For
example,
by
devising
a
transcript
in
which
the
first
AUG
codon
was
in
an
unfavorable
context
and
hence
"leaky,"
we
were
able to
show
that
downstream
©
The
Rockefeller
University
Press,
0021-9525/91/11/887/17
$2
.00
The
Journal
of
Cell
Biology,
Volume
115,
Number
4,
November
1991887-903
secondary
structure
enhances
recognition
of
the
preceding
AUG
codon,
apparently
by
preventing
the
40S
ribosomal
subunit
from
scanning
too
fast
or
too
far
(196)
.
The
contribu-
tion
of
downstream
secondary
structure
would
have
been
missed
had
the
primary
sequence
around
the
first
AUG
codon
been
more
favorable,
and
vice
versa
.
Having
used
the
reductionist
approach
to
identify
several
features
that
can
modulate
initiation,
I
attempt
herein
to
put the story
back
to-
gether
by
examining
the extent to
which
natural
mRNAs
conform
to the
experimentally
determined
requirements
for
initiation
.
A
surprising
realization
is
that,
although
most
ver-
tebrate
mRNAs
have
features
that
ensure
the
fidelity
of
initia-
tion
(i
.e
.,
selection
of the
correct
AUG
codon),
many
do
not
appear
to
be
designed
for
efficient
translation
.
This
would
seem
to
have
important
implications
for
gene
regulation
.
LeaderSequences
on
Vertebrate
mRNAs
:
An
Overview
In
considering
the extent
to
which
natural
mRNAs
conform
to the
five
recognized
requirements
for
initiation,
I
will
focus
on
mRNAs
from
vertebrate
cells
where
the rapidly
expand-
ing
catalogue
of
sequences
provides
grist
for
analysis
.
mRNAs
from
animal
and
plant viruses
and
yeasts
are
men-
tioned
only
incidentally
when
they
uniquely
illustrate
a
point
.
Every
cellular
mRNA
that
has
been examined
is
capped
(355)
.
Not
every
mRNA
has
been
examined,
of
course,
but
it
seems
unlikely
that
uncapped
cellular
mRNAs
will
be
found
inasmuch
as
the
cap
is
crucial
not
only
for
translation
(355) but also
for
mRNA
stability
and
transport (126)
.
Al-
though
the
uncapped
rnRNAs
from
picornaviruses
are a
vogue
topic
for
discussion
(158),
it
should
be
remembered
that
picornaviruses
are
exceptions
.
All
other
animal
viruses
produce
capped
mRNAs,
even
when
doing
so requires the
virus
to
encode
its
own
capping
and
modifying
enzymes
(189)
.
The
requirement
for
a
favorable
context
around
the
AUG
initiator
codon
is
also
met
by
nearly
all
mRNAs
from
higher
eukaryotes
.
The
consensus
sequence
for
initiation
derived
from
a
compilation
of
699
vertebrate
mRNAs
(191)
is
GCC'CC
AUG
G,
the
same
as the
experimentally
derived
optimal
sequence
(187,
190,
194)
.
While
the
full
consensus
sequence
is
found
in
only
a
small
number
of vertebrate
mRNAs,
the
two
positions
most
critical
for function (187)
are
highly
conserved
:
97%
of
vertebrate
mRNAs
have
a
pu-
rine
(usually
A)
in
position
-3
and
46%
have
G
in position
887
on July 10, 2011jcb.rupress.orgDownloaded from
Published November 15, 1991

+4
(191)
.
(The
A
of
the
AUG
codon
is
designated
+1,
with
positive
and
negative
integers
proceeding
3'
and
5,
respec-
tively
.)
Since
context
is
a
principal
determinant
of the
fidelity
of
initiation,
good
adherence
to
the context
rules
ensures
that
the
full-length
protein
is
the
sole
translation
product
from
most
vertebrate
genes
.
Only
six
out
of
699
mRNAs
in
the
aforementioned
survey
(191)
lacked
the preferred
nucleotide
in
both of
the key
positions
flanking the
AUG
codon
.
One
of the
original
six
entries
has
since
been
discounted
as
a
se-
quencing
error (212)
but
a
few
more
mRNAs
have
recently
been
added
to
the
list
(154,
180, 311)
.
These
rare
mRNAs
with
highly unfavorable
initiation
sites
encode
potent
regula-
tory
proteins
(growth
factors,
cytokines,
etc
.),
suggesting
that
a
weak
context
might
be
an
occasional
ploy
to
modulate
the
yield
of proteins
that
could
be
harmful
if
overproduced
.
Parenthetically,
a recent
compilation (unpublished
results)
of
252
plant
mRNA
sequences
reveals
that
93
%
have
a
purine
in
position
-3, and
74%
have
G
in
position
+4
;
thus,
in
the
two
most
influential
positions, plant
and
animal
consensus
sequences
are the
same
.
The
importance
ofposition of
the
AUG
codon
in
determin-
ing
the
site
of
initiation
is
illustrated
by
a
family
of
bifunc-
tional
genes,
described
in
the
next
section,
and
by
the
fact
that
the
first
AUG
codon
is
the
unique
initiation site
in
most
(perhaps
90%
of)
vertebrate
mRNAs
(191)
.
The
list
of
mam-
malian
cDNA
sequences
that
violate
the
first-AUG-rule
is
growing,
however,
and
it
includes
a
large
number
of
critical
regulatory
genes,
as
documented below
.
If
these
AUG-
burdened
cDNA
sequences
actually
correspond
to
func-
tional
mRNAs,
their translation
should
be
compromised
.
If
the
AUG-burdened
cDNA
sequences
correspond
instead
to
mRNA
precursors
or
otherwise
nonfunctional
transcripts
(as
has
been
established
in
some
cases),
their
abundance
implies
considerable
regulation
at
a
level
other
than
translation
.
Both
possibilities
are
discussed
below
.
A
handful
of
natural
mRNAs,
mostly
of
viral
origin,
seem
to
have very
efficient
5'
noncoding
sequences
as
documented
by
leader-shuffling
experiments
(84,
237,
251,
342,
360)
.
At-
tempts
to
pinpoint
a
motif
in
any
of
those
sequences
that
un-
derlies
its
efficient
translation
have
been
notably
unsuccess-
ful
;
that
is,
virtually
every
portion
of
the
5'
noncoding
sequence
has
been
mutated
or
deleted
or
replaced without
impairing
translation
.
The
apparent
absence
of a
discrete
effector
motif,
and
the
fact
that
the
sequences
in
question
are
A
.
PROMOTER
SWITCHING
C
chond"
protein
The
Journal
of
Cell
Biology,
Volume
115,
1991

888
deficient
in
G
residues,
fit
with
the
view
that
a
moderately
long,
unstructured
5'
noncoding
sequence
may
be
necessary
and
sufficient
for
efficient
initiation
of
translation
(199)
.
In-
deed,
with
some
experimental
constructs,
the
simple
trick
of
lengthening
the
5'
noncoding
sequence
improves
translation
by an
order
of
magnitude,
creating
very
efficient
in
vitro
ex-
pression vectors
(199)
.
(The
5'sequences
were
lengthened
by
reiterating
three
different
synthetic
oligonucleotides
which
were
designed
simply
to
preclude
secondary
structure
.
It
seems
unlikely
that
such
arbitrarily
designed
sequences
are
recognized
by
hypothetical
"enhancer
proteins
:"
Rather,
the
observed
accumulation
of extra
40S
ribosomal
subunits
on
long
5'
leader
sequences
(199)
may
underlie
their
transla-
tional
advantage
.)
The
advantage
conferred
by
long,
syn-
thetic
leader
sequences
does
not
hold
for
most
naturally
oc-
curring
leaders,
however
:
5'
noncoding
sequences
hundreds
of
nucleotides
long
are not
uncommon
on
vertebrate
mRNAs,
but
their
remarkably
high
GC
content
implies
that
they are highly structured
;
and
a structured
leader
sequence,
be
it
long
or
short,
is
a
major
barrier
to
translation
(188,
195)
.
The
frequent
presence
of
such
sequences
on
mRNAs
from
critical
regulatory
genes
(see
below) has
notable
impli-
cations
for
gene
regulation
in
vertebrates
.
These
considera-
tions
do
not
extend
to
mRNAs
from
plants
or
budding
yeasts,
which
usually
have
AU-rich,
rather
than
GC-rich,
leader
sequences
.
Bifunctional
Genes
and
Bifunctional
mRNAs
The
importance of
position
in
determining
the
functional
ini-
tiator
codon
is
illustrated
by
a
family
of
genes
that
are
re-
quired
to
produce
two
versions
of the
encoded
protein (Fig
.
1
A
and
Table
I)
.
The
general
idea
is
that
ribosomes
need
to
initiate
translation
from
the
first
and
second
AUG
codons
in
each
of these
genes
.
Although
the
longer
mRNA
from
the
model
gene
in
Fig
.
1
A
contains
both
AUG
codons,
the
pres-
ence
of a
good
context
around
the
first
AUG
codon
precludes
access
to
the
second
.
The
solution
is
that
the
gene produces
a
second
form
of
mRNA,
the
5'
end
of
which
maps
between
the
two
AUG
codons
.
In
each
mRNA
ribosomes
initiate
at
the
first
and
only
the
first
AUG
codon
.
There
is
a
way
for
two
proteins
encoded
in
overlapping
open
reading
frames
(ORFs)
to
be
translated
from
a
single
mRNA
;
namely,
by
introducing
a
poor
context
around
the
first
AUG
codon
.
In
the bifunctional
mRNAs
listed in
Table
B
.
LEAKY
SCANNING
m1G--
cnnAUG----AUG-----------------UAA--3'
4
#1
#2
P
Figure
1
.
T\vo
mechanisms
that
enable
one gene
to
produce
two
versions
of
the
encoded
protein
.
(A)
When
the
first
AUG
codon
is in
a
strong context, as
is
usually
the
case,
one gene can
produce
two
proteins
only
by producing
two
mRNAs,
i
.e
.,
by
initiating
one
transcript
(PI)
upstream
from
the
first
AUG
codon
and
initiating
a
second
transcript
(P
z
)
downstream
from
that
AUG
.
Often
the
NH
Z
-terminal
amino
acid
extension
targets
the
long
form
of
the
protein
to
a
special
intracellular
compartment
.
Examples
are
given
in
Table
I
.
(B)
Leaky
scanning
permits
synthesis
of
two
proteins
from
one
mRNA
when
the
context
around
the
first
AUG
codon
is
unfavorable
; i
.e
.,
when
a
pyrimidine
occurs
in
position
-3,
or
when
there
is
a
Gin
position
-3
and
something
other
than
G
in
position
+4
.
Examples
of
genes
that
use
leaky
scanning
are
given
in
Table
II
.
m1G---AccAUGG----
silent
AUG
x2-----------------UAA--3'
mRNA-1
Q
P
1
-
P2
GENE
m1G---AUG--------------------
UAA--3'
MRNA-2
4
0
1
mi
.c
protein
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Table
I
.
Genes
that
Produce
Two
Overlapping
Proteins
by
Initiating
Transcription
from
Two
Promoters,
as
Illustrated
in
Fig
.
1
A
°
Val-tRNA
synthetase
(VAS1,
yeast)
(49)
°
His-tRNA
synthetase
(HTS1,
yeast)
(282)
°
a-Isopropylmalate
synthase
(LEU4,
yeast)
(18)
°
tRNA
dimethyltransferase
(TRM
1,
yeast)
(90)
°
Serine
:pyruvate aminotransferase
(SPT,
rat)
(291)
°
Cyclophilin
(N
.
crassa) (398,
399)
Anion
transport protein
(band
3,
chick)
(177)
/31-4-galactosyltransferase
(bovine) (234a,
331)
b
Invertase
(SUC2,
yeast)
(43)
Gelsolin
(human)
(207)
b
Surface
antigen,
Hepatitis
B
virus (307)
`
E2
protein,
bovine
papillomavirus
(211)
Family 35
capsid
proteins,
herpes
simplex
(228)
°
Progesterone
receptor
(forms
A&
B,
human)
(167)
Sterol carrier
protein
(SCP
X
&
SCP
2,
rat
liver)
(349)
Porphobilinogen
deaminase
(human)
(55)
Gs(x protein
(human)
(156)
Erythroid
membrane
protein
4
.1
(human)
(68)
Superscripts
refer
to
ways
in
which
the function
of
the
long
isoform
differs
from
that
of
the
shorter protein
:
(a)
import
into
mitochondria,
(b)
secretion,
(c)
control
of
transcription
.
The
expression
of
porphobilinogen
deaminase,
erythroid
membrane
protein
4
.1,
and
G
s
a
protein
requires
alternative splicing
as well as
promoter
switching
;
they
are included
because
the
net
effect
is
acti-
vation
of an
internal
AUG
initiator
codon
by
making
it
the
first
AUG
in
the
mRNA
.
Not
listed
are
some
interesting
genes
that
produce
small
amounts
of
5'
truncated
transcripts
in
extraneous
tissues
(63,
160,
234, 405,
410)
.
Even
when
such
mRNAs
can
be
shown
to
direct
synthesis
of
a
polypeptide
fragment
(63),
which
is
almost
inevitable
if
the
transcript
enters
the
cytoplasm,
the
phenomenon
might
reflect
inadvertent
expression
;
what
needs
to
be
established
is
that
the
NH
2
terminally
truncated
polypeptide
serves
a
unique
function
in
the
ectopic
tissue
.
II,
the
first
AUG
codon
deviates
from
the
consensus
se-
quence
in
either
or
both of
positions
-3
and
+4
.
(Three
ex-
ceptions
are
discussed
in
the
Table
II
legend
.)
The
result
is
"leaky
scanning"
in
which
some
40S ribosomes
bypass
the
Table
11
.
Genes
that
Produce
Two
Proteins
from
One
mRNA
by
Leaky
Scanning,
as
Illustrated
in
Fig
.
1
B
A
.
first
AUG
codon
;
initiation
occurs
from
the
first
and
second
AUG
codons
in
these
mRNAs
(Fig
.
1
B)
.
Curiously,
most
of
these
bifunctional
mRNAs
are
of
viral
origin
.
Only
two
cellular
mRNAs
are
listed in
Table
II,
and
in
neither
of
those
cases
has
the
short protein
been
shown
to
mediate a
function
distinct
from
the
long
isoform
.
Thus,
as
a
practical
device
for
producing
two
proteins
from
one
gene,
cells
rely
mostly
on
a
transcriptional
device
(Fig
.
1
A) while
viruses
use a
translational
ploy
(Fig
.
1
B)
.
Leaky
scanning
does
not
re-
quire
virus-induced
modifications
of
the translational
ma-
chinery,
however,
inasmuch
as
the
isolated
reovirus Sl
gene,
when
expressed
in
uninfected
COS
cells,
produces
the
ex-
pected
two
proteins
(95)
.
Leaky
scanning
may
also
result
when
the
first
AUG
codon
resides
close
to
(within
12
or
so
nucleotides
of)
the
cap
(113,
198),
although
leakiness
due
to
an
unfavorable context
is
the
more
common
mechanism
.
Not
included
in
Table
II
are
a
few
bifunctional
mRNAs
(344,
347,
397)
in
which
two
proteins
are
produced
from
nonoverlapping
ORFs
.
In
such
cases,
reinitiation
as well as
leaky
scanning
may
provide
access
to
the
second
AUG
codon,
and
the
contributions
of
the
two
processes
are
hard
to
sort
out
.
As
explained
elsewhere
(192,
200),
reinitiation
by
eukaryotic
ribosomes
is
usually
inefficient
and
seems
to
occur
only
when
the
5'
proximal
ORF
is
small
.
Those
re-
strictions
probably
explain
why
no
bifunctional
mRNA
has
been
identified
in
animal
cells
or
viruses
that
relies
exclu-
sively
on
reinitiation
for
expression
of
the
downstream
cis-
tron
.
There
are
quite
a few
viral
mRNAs
that
are
structurally
bicistronic,
encoding
two
full-length
proteins
in
nonoverlap-
ping
ORFs,
but
they
are
functionally
monocistronic,
trans-
lating
only
the
5'
proximal
ORF
(189)
.
In
the
case
of
Epstein-
Barr
virus,
a
bicistronic
mRNA
that
encodes both
the
R
and
EBl
proteins
(in
that
order)
does appear
capable
of
trans-
lating
EBl,
albeit
inefficiently
;
however,
the
virus
also
pro-
duces an abundant
transcript
that
encodes
(and
translates
efficiently)
only
EBl
(243)
.
The
same
is
true
for
synthesis
In
several
cases
the
connection
between
leaky
scanning
and
a
suboptimal
context
around
the
first
AUG
codon
has
been
confirmed
by
mutational
analysis
(78,
95,
346,
370)
.
Only
three cases
have
been described
in
which
ribosomes
initiate at
the
first
and
second
AUG
codons
despite
a
favorable
context
around
the
first
AUG
.
The
most
important
of
these
exceptions
is
influenza
virus
B,
where
the
proximity
of
the
second
AUG
codon
to
the
first
AUG
seems
to
allow leaky scanning
(414)
.
The
other
exceptions
are
barley
stripe
mosaic
virus (308)
and
cowpea
mosaic
virus
RNA-M
(144),
where
the
absence
of secondary
structure
downstream
from
the
first
"strong"
AUG
codon might
account
for
the
leakiness
.
Leaky
scanning
in
those
two
plant
viruses
might be
inadvertent,
inasmuch
as
the
second
protein
isoform
does
not
contribute to
viral
infectivity
.
In
contrast,
for
most
of
the
other
viral entries,
both
proteins
produced from
the
bifunctional
mRNA
are required
for
infectivity
.
The
fact
that
the
overlapping
arrangement
of
ORFs
is
conserved
among
different
members
of
the
paramyxovirus,
reovirus,
bunyavirus,
adenovirus,
rotavirus,
and
tymovirus
families
constitutes
additional
evidence
that
the
synthesis
of
two
proteins
by
leaky scanning
is
not
accidental in
those cases
.
In
the
case
of HIV-1,
vpu
functions
more
efficiently
in
promoting
the
processing
of
env
when
the
two
proteins
are
translated
from
the
same
mRNA
than
when
they
are
expressed
experimentally
from
separate
transcripts
(M
.
Martin,
K
.
Strebel
and
R
.
Willey,
personal
communication)
.
An
asterisk,
preceding
some
entries
in
the
table,
means
that
only
one
of
the
two
proteins
predicted
by
the
mRNA
sequence
has
been
detected so
far
.
Kozak
An
Analysis
of
Vertebrate
mRNA
Sequences

88
9
Initiation
at
15'
and
2"°
AUGs
generates
long
and
short
B
.
Initiation
at
1"
and
2"°
AUGs
in
different,
overlapping
protein isoforms
from
the
same
reading
frame
:
reading
frames
produces
two
unrelated
proteins
:
Simian
virus
40
late
19S
mRNA
-
VP2,
VP3
(346) Sendai
(paramyxo)virus
-
P,
C
(78)
Rotavirus
SAIL,
segment
9
-
37K, 35K,
(VP7)
(47,
370) Reovirus
S
1
mRNA
-
al,
14K
(92,
95)
West
Nile
flavivirus
-
V2
core
proteins
(44)
Bunyavirus
s-RNA
-
N,
NS
s
(109)
Dengue
(type
3)
flavivirus
-
C,
C'
(300)
Adenovirus,
region
EIB
-
21K,
55K
(27)
Foot-and-mouth
disease
virus
-
p20a,
P16
(64)
Adenovirus,
region
E3
-
6
.7K,
gp19K
(415)
Hepatitis
B
virus,
human
-
pre-S,
p24s
(306)
Human
T-Cell
Leukemia
Virus
(HTLV-I)-
p27,
p40
(279,
359)
Feline
leukemia
virus
-
gPr80gag,
Pr65gag
(214)
Human
Immunodeficiency
Virus
Type
I -
vpu,
env
(345)
Rift
Valley fever (bunya)virus
-
M
proteins
(378)
Potato
leafroll
luteovirus
-
CP, 17K
(380)
Cucumber
necrosis virus
-
p21,
p20
(325)
Satellite
tobacco
mosaic
virus
-
6
.8K, 17
.5K
(261)
Cowpea
mosaic
virus
RNA-M
-
105K,
95K
(144)
Rotavirus
SA11,
segment
11
-
28K,
I
IK
(249,
263)
Barley
stripe
mosaic
virus
-
(3b,
/3b'
(308)
*Turnip
yellow mosaic
(tymo)virus
-
69K
OP,
200K
RP
(170)
Creatine
kinase,
chicken
brain
(363)
*Maize
chlorotic
mottle virus
-
p31
.6,
p50
(290)
N-myc,
human
tumor
cell
lines
(240) Influenza
B
virus
-
NB,
NA
glycoproteins (414)
on July 10, 2011jcb.rupress.orgDownloaded from
Published November 15, 1991

of the
LP
and
EBNA-2
proteins
of
Epstein-Barr
virus
(5)
.
The
functionality
of an
interesting
bicistronic transcript
for
growth/differentiation
factor
1
has not
yet
been
established
.
(Although
the
only
detected
transcript
for
GDF-1
in 14.5-d
mouse
embryos
is
a
3-kb
bicistronic transcript
in
which
GDF-1
is
the
downstream
cistron,
the
GDF-1
protein
de-
tected
by
immunohistochemical
analysis
in
14
.5-d
embryos
might
actually
have
been
synthesized
a
few
days
earlier,
when
a
1
.4-kb
transcript
was
the
predominant
form
(218)
.)
The
ability
to
reinitiate
to
some
extent
after
translating
a
small
5'
ORF,
and
the
tendency
of
40S
ribosomes
to
scan
past
an
AUG
codon
in
aweak
context,
explain
how
ribosomes
can
initiate
from
an
AUG
codon
that
is
not
first
.
Nevertheless,
the
occurrence
of
upstream
AUG
codons
nearly always
reduces
the
efficiency
of
initiating
from
downstream
.
Thus,
mRNA
(or,
more
correctly,
cDNA)
sequences
that
are
pep-
pered
with
small
upstream
ORFs
pose
a
problem
.
5'
Noncoding
Exons,
Introns,
and
Upstream
AUG
Codons
The
simple
question
of
whether
the
mRNA
from
a
particular
gene
has
upstream
AUG
codons cannot
always
be
answered
simply
.
Some
of
the
complexities
are
due
to
5'
noncoding
exons
and
associated
phenomena
such
as
alternative
splic-
ing,
inefficient
removal
of a
5'
intron,
and
the
presence
of
al-
ternative
promoters
.
I
will
first
address
those complications
and
then
try
to
assess
the
frequency
and
significance
of
up-
stream
AUG
codons
in
vertebrate
mRNAs
.
Nearly
one-fourth
of the
entries
in
a
recent
survey
of
699
vertebrate
mRNA
sequences
(191)
have
turned
out
to
have
an
intron
between
the
promoter
and
the
start
of the
major
ORF
.
The
high
incidence
of
5'
introns
has
theoretical
as
well
as
practical
consequences
.
The
first
intron in a
gene
some-
times
contains
sequences
that
facilitate
transcription
(26,
42,
60, 73,
150,
174,
176, 185,
269, 280, 287, 303, 368),
an
effect
that
sometimes
requires the intron to
be
near
the
5'
end
(42,
287,
303)
.
Some
genes
that
have
retained
a
5'
intron thereby
have
the
ability
to
switch
promoters,
in
response
to
hormonal
or
tissue-specific
inducers,
for
example,
and
thus
to
ex-
change an
inefficiently
translated
5'
noncoding
exon
for
one
that
appears
more
favorable
(9,
54,
77,
106,
289)
.
(The
predicted
improvement
in
translation
has
not
yet
been
verified
for
all
of
those
genes
.)
Another
kind
of regulation
takes
the
form
of
allowing
a
gene
to
be
transcribed
in
an
ec-
topic
tissue
but
preventing
its
translation
by
not
removing
the
5'
intron
.
The
expression
of
gonadotropin-releasing
hor-
mone
mRNA
in
extra-hypothalamic
tissues
is
a
striking
ex-
ample
(135)
.
Another
might
be
the
expression
of the tyrosine
kinase
fer
gene
in
testis
versus
other
tissues
(101)
.
From
a
practical
perspective,
the
frequent
presence
of
5'
introns
(sometimes
directly
abutting
or even
interrupting
the
AUG
codon)
necessitates
caution
in
picking
a
probable
start
site
for translation,
and
caution
in
scoring
upstream
AUG
triplets
.
Many
claims
of
mRNAs
with
AUG-burdened
5'
non-
coding
sequences
(46,
114, 125,
213, 236, 238,
292,
348,
387) have
been
resolved
by
finding
that
the
5'
portion
of
the
cDNA
corresponds
not
to the
mature
mRNA
but
to
an
intron-containing
form
(36,
135,
225, 235,
284,
316, 388,
407,
408)
.
(see reference
193
for
additional
examples
.)
The
growing
evidence
of
incomplete
(20,
23,
28, 74,
76,
80,
138,
151, 168,
222,
259, 343,
354,
411) or regulated (417)
RNA
processing
in
mammalian
cells
underscores
the point
that
The
Journal
of Cell
Biology,
Volume
115, 1991
cDNA
sequences cannot
invariably
be
equated with
func-
tional
mRNAs
.
Some
intron-containing
transcripts
are
abun-
dant
(70),
some
enter the
cytoplasm
(328),
and
some
are
even
found
on
polysomes
(411)
.
These
problems
complicate
attempts to
deduce
the
real
structures
of vertebrate
mRNAs
.
While
a
cDNA
sequence
that
retains
an
unspliced
intron
within
the
coding
domain
is
easily
recognizable
as a process-
ing intermediate, the
presence
of
unspliced
intron(s)
in
the
5'
noncoding
domain
is
much
harder
to
recognize
.
Some
genes
are
transcribed
in
ectopic
tissues
froman
ill-
placed
promoter
that
burdens
the
5'
noncoding
sequence
with
AUG
codons, thereby
impairing
translation
in
that
par-
ticular
tissue
.
In the
tissue
that
constitutes
the
major
site
of
expression,
however,
a
different
promoter
produces
a
5'
non-
coding sequence
that
is
not
so
encumbered
.
Examples
in-
clude
murine
complement-B
mRNA
in hepatic
versus
ex-
trahepatic
tissues
(286),
rat
preproenkephalin
mRNA
in
testis
versus
brain
(172, 175),
rat
a-crystallin
mRNA
in
brain
versus
other
tissues
(157),
and
rat
farnesyl
pyrophos-
phate
'synthetase
mRNA
in
liver
versus
testis
(390)
.
In the
last
three cases,
the
predicted
difference
in
translational
efficiency
has
been
verified
experimentally
.
Another
ploy
in-
volves
switching
to a
shorter,
more
efficiently
translated
leader
sequence
in
response
to
some
developmental
(61,
425)
or
environmental
cue,
such
as
stimulation
with
serum
(409)
or
retinoic
acid
(61)
or
endotoxin
(286),
or
during
T
cell
maturation
(324)
.
Because
of
promoter
switching
and/or
alternative
splicing,
many
other vertebrate
genes
produce
multiple
transcripts
that
differ
near
the
5'
end,
and
failure
to
detect
all
pertinent
forms
has
sometimes
led
to
false
conclu-
sions
.
The
suggestion
of
"internal
initiation"
in the
chicken
progesterone
receptor
mRNA
(71)
is
one
example
of a
wrong
conclusion
that
was
righted
upon
discovering
other
forms
of
mRNA
(166,
167)
.
Detecting
alternative
transcripts
is
not
al-
ways
easy!
Competition
for
the
primer
may
cause
a
minor
transcript
to
be missed
(175)
.
Even
the
major
transcript
has
been
missed
when
the
primer
was
positioned
inappropriately
(72)
or
when
hybridization
conditions
were
too
stringent
(338)
.
Because
of
the
difficulties
described
above
and
various
other complications
in
cloning
or
interpretation
(6,
32,
37,
68,
69,
146,
226,
430),
the
frequency
of
spurious
upstream
AUG
codons
in
vertebrate
mRNAs
is
difficult
to estimate
;
but
clearly
it is
not
as
high
as
superficial
reading
of
the
litera-
ture
might
suggest
.
When
upstream
AUG
codons do
occur,
the
AUG-burdened
leader
sequence
impairs
translation
(9a,
12,
105, 157,
247,
272,
277, 281, 326, 390,
409, 412,
424),
as
expected
if initiation
occurs
by
the
conventional
scanning
process
.
A
partial
listing
of
cDNAs
with
AUG-burdened
leader
se-
quences
is
given
in
Table
III
.
It
includes
many
proto-
oncogenes
as
well
as
genes
for
transcription
factors,
a
variety
of
receptor
proteins,
signal
transduction
components,
and
many
proteins
involved
in the
immune
response
.
One
con-
clusion
might
be
that
mRNAs
that
encode
critical
regulatory
proteins are
intended
to
be
translated
poorly
.
I
suspect
that
conclusion
is
true
for
some
entries
in
the table,
but
some
(perhaps
many)
entries
might
reflect
a
different
type
of regu-
lation
.
For
example,
the
repeated
finding
of
incompletely
spliced
transcripts
in
lymphocytes
(20, 107,
389, 411)
and
re-
cent
evidence
that
undefined
posttranscriptional
processes
improve
upon
mitogen
activation
of
lymphocytes
(67) en-
890
on July 10, 2011jcb.rupress.orgDownloaded from
Published November 15, 1991

Table
III
.
Vertebrate
cDNA
Sequences
that
Have
Three
or
More
AUG
Codons
Upstream
from
the
Major
Open
Reading
Frame
Tumor
associated
(proto-oncogenes,
etc
.)
*
abl,
human
(21)
*
bcl-2,
human
(401)
ear-7,
human
(266)
*
erb-A,
human
(413)
erg,
human
(320)
Evi-1,
human
(271)
Evi-2,
mouse
(38)
*
fgr,
human
(122)
#
fos-B,
mouse
(427)
HCK,
human
(318)
*# int-2,
human
(34)
*
lck,
mouse
(324)
*
mos,
mouse
(314)
ROS-1,
human
(22)
*#
sis,
(PDGF-2)
(98,
319)
*
sno,
human
(285)
syn
(slk),
human
(352)
*
T-cell
l
1p15
(25)
Immune/inflammation
mediators
Interleukin-7,
mouse
(239,
281)
IL-1
receptor,
mouse
(358)
IL-2
receptor-$,
human
(132)
IL-3
receptor,
mouse
(116)
IL-5
receptor,
mouse
(382)
IL-6
receptor,
human
(420)
IL-7
receptor,
mouse
(309)
G-CSF
receptor,
mouse
(108)
C3b
receptor
(Mac-la)
(315)
CD28,
human
T
cells
(217)
CD75, human
B
cells
(365)
Ly-5
(CD45,
CALLA)
(334)
Ttg-1,
T
cells
(252)
Surface
antigen
l14/A10
(87)
Tyr
kinase,
leukocyte
(19)
,6Fcy
receptor
11,
mouse
(143)
IgE
receptor
(high
affin)
(229)
Kozak
An
Analysis
of
Vertebrate
mRNA
Sequences
Signal
transduction
courage
the
idea
that
many
cDNA
sequences
from
immune
cells
might
correspond
to
precursors
rather
than
to
func-
tional
mRNAs
.
The same
may
be
true
of
AUG-burdened
transcripts
from
transcription factor
genes,
since
some
of
those
transcripts
are
restricted
to
the
nucleus
(61,
70,
275)
;
in
other
cases,
a
transcript
is
detectable
but the
correspond-
ing
protein
is
not
(256)
.
The
first
report
of
mitogen-regulated
splicing
of
5'
introns
in
vertebrate
genes
has
just
been
pub-
lished
(417),
giving
substance
to the
hypothesis
that
non-
translatable
transcripts
may
be
synthesized
and
stored
for
later
processing
.
Proto-oncogenes,
on
the other
hand,
might
be
genuine
candidates
for
translational
modulation
via
an
encumbered
chick
embryo
tyr
kinase
(304)
mouse
liver
tyr
kinase
(244)
FER
tyr
kinase
(130)
tyk2
tyr
kinase
(100)
elk
tyr
kinase
(223)
ERK3
ser/thr
kinase
(29)
p58
protein
kinase
(173)
rp-S6
kinase,
chick
(4)
protein
tyr
phosphatase
(PTPase)
LRP
(293)
PTPase,
megakaryocyte
(121a)
Phospholipase
C-1,
rat
(375)
cAMP
phosphodiesterase
(230)
insulin
receptor
substrate-I
(IRS-1,
pp185)
(376a)
89
1
#
Thyroid
hormone,
rat
(277)
Rev-ErbAoi,
rat
(216)
Thyroid
hormone,
rat
(394)
*
Thyroid
hormone,
human
(391)
Growth
factors
Keratinocyte
GF
(99)
*
Insulin-like
GF-1
(17,
105)
Platelet-derived
GF-A
(328)
Epidermal
GF
(16)
#
Transforming
GF-03
(9a,
209)
See
also
:
proto-oncogenes
Some,
perhaps
many,
of
these
cDNA
sequences
are
likely
to
represent
mRNA
precursors
rather
than
functional
mRNAs
(see
text)
.
The
literature
contains
scattered
reports
of
AUG-burdened
cDNA
sequences
in
addition
to
those
listed
here
.
*,
The
gene produces
multiple
transcripts
with
alternative
5'
noncoding
sequences
;
#,
translation
is
more
efficient
with
transcripts
(natural
or
derived)
that
lack
the
encumbered
leader
sequence
.
leader
sequence
.
Interpretation
is
complicated
by
the
fact
that
many
proto-oncogenes
produce
transcripts
with
alterna-
tive 5'
sequences
(these
are
marked
by
asterisks
in
Table
III),
but
several
observations
support
the idea
that
proto-
oncogene
mRNAs
are
meant
to
be
translated
inefficiently
:
c-mos
transcripts
are
found
on very
small
polysomes
(314)
;
some
activated
oncogenes
produce
transcripts
with
simpler
5'
noncoding
sequences
than
the
corresponding
proto-
oncogenes
(321,
337)
;
and
the
experimental
expression
of
many
proto-oncogenes
improves
dramatically
upon
deleting
portions
of
the
leader
sequence
(12,
50,
247,
319)
.
To
pro-
pose
that
proto-oncogene
n1RNAs
might
be
translated
by
a
mechanism
other
than
scanning
(253),
inasmuch
as
their
Transcription
factors
and
DNA-binding
proteins
Receptors
for the
following
ligands
NF1-B (TGGCA),
chicken
(330)
*
Acetylcholine,
rat
(224)
NFI-X,
hamster
(112)
*
Angiotensin
H,
rat
(276)
CAMP
response
(CRE-BPI)
(278)
#
Atrial
natriuretic
peptide
(110)
IFN
response
(IRE-BFI)
(421)
D,
dopamine,
mouse
(268)
PRDII-BFI
(96)
Estrogen,
chicken
(203)
DBP,
rat
liver
(272)
GABA
A
al,
mouse
(171)
HOX
2G,
human
(2)
GABA
A
y2,
chicken
(115)
HOX
5
.1,
human
(61)
Gastrin-releasing
peptide
(13)
Hox
2
.9,
mouse
(274) Glycine,
human
brain (119)
Hox
3,
mouse
(31)
Heparin-binding
GF
(K-sam)
(133)
Hox
3.1,
mouse
(10)
Interferon
a,
human
(402)
Hox
3
.2,
mouse
(93)
Progesterone,
rabbit
(262)
*
BTF3
(general)
(428)
Prolactin,
rabbit
(89)
OTF-2,
human
(339)
Retinoic acid
(hRAR-a)
(30)
TFE,
canine
(161)
*
Retinoic
acid
(mRAR-S)
(426)
KUP,
human
(48)
*
Retinoic
acid
(hRAR-y)
(204)
poll
factor
UBF,
rat
(296)
Serotonin
lc, rat
(164)
HNF-1(3,
mouse
(256)
Serotonin
5HT-2,
rat
&
CHO
(45,
313)
Substance
K,
bovine,
human
(111,
248)
Substance
P, rat
(136)
#
Thromboxane
A
Z ,
human
(140)
on July 10, 2011jcb.rupress.orgDownloaded from
Published November 15, 1991

AUG-burdened
leader
sequences
seem
incompatible with
efficient
scanning,
is
to
miss
the point
that
these
potent
pro-
teins
probably
have
to
be
translated
inefficiently
.
Occurrences
and
Consequences
of
Secondary
Structure
The
catalogue
of vertebrate
mRNAs
with
GC-rich
(hence
highly
structured)
leader
sequences
again
includes
many
mRNAs
for
oncoproteins,
growth
factors,
transcription
fac-
tors,
signal
transduction
components,
and
a
wide
variety
of
receptor
proteins
(Table
IV)
.
Again,
the
presence
of an
en-
cumbered
leader
sequence
suggests
that
production
of these
critical
regulatory
proteins
is
throttled
at
the
level
of
transla-
tion
.
The
GC-cohort
also
includes
many
housekeeping
genes,
which
are generally
recognized
to
be
expressed
at
low
levels
.
While
it
is
easy
to
show
that
many
of
these leader
se-
quences
support
translation
poorly
(see
below),
delineating
the
cause
is
not
simple
.
The
extraordinarily
high
GC
content
(70
to
90%)
predicts
many
alternative
base
pairings,
making
it
impossible
to pinpoint
a
target
for
mutagenesis
.
Conse-
quently,
our understanding
of
how
particular
base-paired
structures
affect
translation
relies
heavily
on
experiments
carried out
with
synthetic
transcripts
(188,
195,
196)
in
which
discrete
stem-and-loop
structures
have
been
intro-
duced
and
their
existence
documented
by genetic
techniques
.
The
best
evidence
that
mRNAs
in
Table
IV
are
translation-
ally
impaired
is
the
dramatic
improvement
in
expression
when
the
GC-rich
leader
sequences
(some
of
which
also
con-
tain
upstream
AUG
codons)
are
truncated experimentally
(53,
82, 182, 221,
246,
273, 319,
395)
.
(Discrepancies
be-
tween
mRNA
levels
and
protein
accumulation
in
some
stages
or conditions
of
cell
growth
may
be
another
indication
of
translational
control of
transcription factor
and
other
such
genes
(66,
81, 83,
205,
340,
357,
373)
;
but
in
most
of those
cases
alternative
explanations,
such
as
compartmentaliza-
tion
of
the
mRNA
or
accelerated
degradation
of the
protein,
have
not
been
ruled out
.)
Some
genes
in
Table
IV
actually
produce
two
versions
of
mRNA,
on
one
of
which
the leader
is
shorter
and
less
encumbered
than
on
the
other
(178,
283,
317,
377)
.
In the
few
cases
where
long-
and
short-leader
mRNAs
from
the
same
gene
have
been
put
to
the
test,
the
short-leader transcript
nearly
always
supports
translation
more
efficiently
(153,
283,
337,
409)
.
Indeed,
the
dis-
crepancy
in
translatability
dependent
on
5'
leader
sequences
can
be so
profound
that
a
minor
transcript
from
certain
genes
appears
to
be
the
major
functional
mRNA
(149,
264, 283)
.
Other genes
in the
GC-rich
cohort
produce
transcripts
with
so
many
different
leader
sequences
(75,
85a,
165,
220, 245,
426)
that
it is
impossible
to guess,
andno
small
task
to
test,
their
functionality
.
Notwithstanding
those
caveats,
the
extraordinary
number
of
mRNAs
with
GC-burdened
leader
sequences
forces the
idea
that
synthesis of
critical
cellular
proteins
is
probably
throttled
at
the
level
of
translation
.
Under
constitutive
condi-
tions,
the
synthesis
of
a
single
molecule of such
a protein
could
conceivably
take
hours
as a
40S
subunit
slowly
maneu-
vers
its
way
to the
downstream
AUG
codon
.
If
slow
initiation
of
translation
is
a
key
to
limiting
the
production
of
proteins
that
would
be
lethal
if
overproduced,
one
should
not
be
sur-
prised
that
such
mRNAs
are
virtually
untranslatable in
stan-
dard
in
vitro
assays in
which
mRNAs
are
expected
to pro-
duce
a
product
in
minutes!
A
compelling
rationale
for the
The
Journal
of
Cell Biology,
Volume
115,
1991
cumbersome
5'
noncoding
sequences
on
so
many
regulatory
genes
is
that
those
transcripts
should
respond
as
a
cohort
to
shifts in
the
cell's
translational
capacity
.
As
for
how
hypothet-
ical shifts in
translational
capacity
might
be
accomplished,
changes
in
the
extent
of
phosphorylation
of
initiation
factors
and
ribosomal
proteins
have
often
beenremarked
(137,
393)
.
With
the
notable exception
of
eIF2
(65),
however,
hard
evi-
dence
for
the
functional
consequences of
phosphorylation
remains
elusive
.
A
structured leader
sequence
may
have
qualitative
as well
as
quantitative
effects
on
translation
.
In a small
number
of
vertebrate
mRNAs,
ribosomes
initiate
at
a
non-AUG
codon,
such
as
ACG,
CUG,
or
GUG
(3,
20,
86,
103, 127,
219,
232a,
336)
.
The
list is
slightly
longer
if
one
counts
viral
mRNAs
(15,
78,
312, 367)
.
It is
not
valid,
however,
to
count
mRNAs
in
which
the
use
of
alternative
initiator
codons
has
been
documented
only
in vitro,
where
inappropriate
reaction
con-
ditions
can
activate
cryptic
sites
that
would
not
be used
in
vivo
(194)
.
Initiation
at
non-AUG
codons
is
usually
inefficient
and
usually
occurs
in
addition to
using
the
first
AUG
codon
.
The
result
is
synthesis
of an
"extra"
NH
Z
ter-
minally
extended
version
of the protein
.
(There
are
only
two
instances
in
which
a protein
derives
uniquely
from
initiation
at
an upstream
non-AUG
codon
and
not,
at
least
in
part,
from
the
first
in-frame
AUG
codon
.
One
occurs
in
cells
trans-
fected
with
ltk
tyrosine
kinase
cDNA,
in
which
five
out-of-
frame
AUG
triplets
occur
between
the putative
CUG
initia-
tion
site
and
the
first
in-frame
AUG
(20)
;
initiation at
the
far-upstream
CUG
codon
thus
circumvents
the
problem
of
getting
past
out-of-frame
AUG
codons
.
As
yet,
however,
ini-
tiation
at
the
upstream
CUG
codon
has
not
been
demon-
strated
with
the
endogenous
ltk
gene
in
untransfected
cells
.
The
other
very
intriguing
example
is
the
apparently
unique
use
of
an
AUU
codon
to
initiate
translation
of the
human
en-
hancer
factor
TEF-1
(416)
.)
All of
the
vertebrate
mRNAs
that
use
a
nonstandard
initiator
codon
have
GC-rich
leader
sequences,
prompting
the speculation
that
the
slow
transit
of
scanning
40S
ribosomes
across a highly
structured
5'
non-
coding sequence
might
be
responsible
for
activating
cryptic
upstream
sites
(196)
.
Indeed,
initiation
at
upstream
non-
AUG
codons
in
synthetic
transcripts
was
considerably
en-
hanced
upon
introducing
secondary
structure
in
an
appropri-
ate
position
3'
of
the
cognate
initiator
codon
(196)
.
While
the
NH
Z
terminally
extended
polypeptides
initiated
from
non-
AUG
sites
in
viral
and
cellular
mRNAs
occasionally
have
distinct
functions
(15,
312, 367)
or
distributions
(3,
40,
232a),
it
would
be
simplistic
to
assume
that
every
instance
of
initiation
from
a cryptic
upstream
site
is
functionally
im-
portant
.
Given
the
GC-richness
of
leader
sequences
on
mammalian
mRNAs,
spurious
upstream
initiation
events
may
be
unavoidable
byproducts
of the
way
eukaryotic
ribo-
somes
arrive
at
the
AUG
codon
.
In
avian
cells,
the
efficiency
of
initiating
at
the
upstream
CUG
codon
in
c-nryc
mRNA
is
regulable
by
culture
conditions
(Stephen
Hann,
personal
communication)
.
This
suggests
interesting
modulation
of the
translational
machinery, but
it
does
not aid the
so-far
unsuc-
cessful
effort to
ascribe
functional
significance
to the
NH
Z
terminally
extended
form
of
c-myc
.
Many
vertebrate
mRNAs
that
have
highly
structured
leader
sequences
also
have
upstream
AUG
codons
(see
the
entries
marked
t
in
Table
IV)
.
This coincidence
might
be
viewed
in
either
of
two
ways
.
One
rationalization
invokes
the
89
2
on July 10, 2011jcb.rupress.orgDownloaded from
Published November 15, 1991

Table
IV
.
Some
Vertebrate
Genes
Predicted
to
Have
Highly
Structured
S'
Noncoding
Sequences
Tumor
associated
(proto-oncogenes,
etc
.)
t
bcl-3,
human
(294)
t§
BCR,
human
(353)
bmk,
mouse
(145)
DBL,
human
(94)
$*
erbA-1,
human
THRA
(215)
erbB
(HERD
(124)
eph,
human
(139)
ets-2,
human
(250)
Jos,
human
(372)
$
hck,
mouse
(232)
t
HER2
(neu)
human
(384)
f
hst,
human
(423)
f
int-1,
human
(406)
$§* int-2,
human
(34,
120)
jun,
human
(8)
t
KS
(Kaposi)
(79)
lyl-1,
human
(255)
lyn,
human
(419)
myb,
mouse
(362)
Transcription
factors
and
DNA-binding
proteins
RAP30/74
(general)
(364)
f
NF-KB,
human
(258)
PUA,
mouse
B
cells
(181)
EFI
A
CCAAT-BP,
rat
(301)
CCAAT/EBP,
mouse
(57)
f
NF-Elb,
chicken
eryth
.
(418)
GATA-1
(NF-E1),
human
(429)
GATA-1
(NF-El),
chick (129)
GATA-3,
human
(141)
t
Krox-24,
mouse
(219)
jun-D,
mouse
(332)
f
zif/268,
serum
induced
(56)
hepatocyte
NF-1,
mouse
(205)
t
Cdx-1,
mouse
homeobox
(88)
LAP,
rat liver
(81)
LRF-1,
regen
.
liver
(152)
f*
SCL,
human
(9)
Oct6,
mouse
embryo
(254)
t
Serum
response
(SRE-BF)
(288)
TFIIS
(elongation) (422)
t
TCF-1,
murine
T-cells
(298)
t
TEF-1,
human
EBP
(416)
SCIP
rat
nerve
(204a)
t
L-myc,
human
(169)
t*
N-MYC,
human
(366)
pint-1,
human
(323)
*
H-ras,
human
(148)
Ki
-ras,
mouse
(142)
RB,
human
(147)
rel,
chicken
(128)
t ret
(381)
f*§
sis
(PDGF-2)
human
ski,
human
(285)
t
Spi-1,
human
(322)
* src,
chicken
(85a)
$
syn,
human
(352)
GA733
antigen
(227)
GA733-2
antigen
(379)
mdm-1,
mouse
(361)
mdr-2,
mouse
(121)
timp-2,
human
(369)
f
Wilms'
tumor (WTI)
(39)
(See also
:
growth
control,
receptors)
Signal
transduction
Kozak
An
Analysis
of
Vertebrate
mRNA
Sequences

893
(98,
319)
GAP,
bovine
(403)
G
protein
G
a
l
l,
mouse
(374)
G
protein
G,a,
human
(201)
G
protein
G
;a,
human
(14)
t
G
protein
Ga12,
mouse
(374a)
G
protein
Ga13,
mouse
(374a)
G
protein
02,
human
(104)
$
adenylyl
cyclase,
bovine
(202)
protein
kinase
C
(PKCa)
(329)
PKC-r,
rat
brain (297)
$
PKC-L,
human
(11)
t
nPKC,
rabbit
brain (295)
cAMP-dependent
PKCa,
hu
(241)
cAMP-dependent
PKCO,
mu
(58)
CaM-kinase
II,
rat
(396)
ltk
tyr
kinase,
mouse
(20)
t
PTPase
(R-PTP-a),
mouse
(335)
PTPase,
human
placenta
(52)
prot
.
phosphatase
2A,
pig
(371)
prot
.
phosphatase
2C,
rat
(386)
phospholipase
C-
,
y,
human
(41)
Receptors
for the
following
ligands
t
n-acetylcholine,
a5
(28)
t
n-acetylcholine,
02
(7)
f
a2B-adrenergic,
rat
(102)
*
ß,-adrenergic,
rat
(356)
$§
02-adrenergic,
human
(91)
$
aIA-adrenergic,
human
(233)
*§
atrial
natriuretic
peptide
(53)
f
dopamine
D2,
rat
(267)
t
ear-2
(THR
family) (265)
t*
estrogen,
human
(118)
t
HER3
(EGFR-related)
(310)
$
insulin,
human
(351)
IGF-II,
human
(270)
integrin,
chicken
(385)
interferon-y
(117)
f
interleukin-1
(59)
mannose-6-phosphate
(231)
N10
(TH
receptor
family)
(333)
nerve
growth
factor
(350)
poliovirus,
human
(184)
t*
progesterone,
chicken
(162)
f*
retinoic
acid
(hRAR-y)
(204)
ryanodine,
rabbit
(383)
syndecan,
human
(242)
thrombin,
human
(404)
t*
transferrin,
human
(341)
tumor
necrosis
factor
(183)
(See also
:
proto-oncogenes)
Growth
control
TGF-a,
rat
(24)
*
TGF-ß
1,
human
(178,
317)
t
TGF-ßl
masking
protein
(400)
TNF-ß,
human
(257)
CSF-1,
human
(208)
interleukin
11,
human
(305)
endothelial
GF
(hPD-ECGF)
(123)
t
Egr-1,
mouse
(376)
f
erythropoietin,
human
(159)
basic
fibroblast
GF,
human
(1)
$§
fibroblast
GF-5,
mouse
(12,
134)
*
IGF-II,
human
(155)
IGF-binding
prot-1,
human
(33)
IGF-binding
prot-2,
rat
(35)
t*
PDGF-A,
human
(328)
Schwannoma-derived
GF
(180)
TAPA-1, human
(299)
(See
also
:
proto-oncogenes)
The
leader
sequences
on
cDNAs
from
these
genes
have
a
G+C
content
of 70
to
90%,
which
would
seem
to
imply
extensive
secondary
structure
.
Most
but
not
all
genes
for
oncoproteins,
receptors,
transcription
factors
and
signal
transduction
components
belong
to
this
GC-cohort
.
Overall,
only
19%
ofthe vertebrate
mRNAs
compiled
in
reference
191
have
GC-rich
leader
sequences
.
Of
these,
-40%
fall
into the
categories
listed
in
Table
IV,
although
oncogenes,
receptors,
transcription
factors,
signal transduction,
and
growth
factor
genes
constitute
only
13%
of
the
total
sequences
in
the
compilation
.
Another
-30%
of
the
GC-burdened
leader
sequences
in
reference
191
derive
from
mRNAs
for
cytoskeletal
and
housekeeping
proteins
.
Thus,
GC-rich
5'-noncoding
sequences
are not
randomly
distributed
among
vertebrate
genes
.
The
frequency
of
GC-rich
mRNAs
does
appear
to
be
increasing,
however,
now
that
technical
improvements
enable
the routine
cloning
of
cDNAs
derived
from
scarce
transcripts
.
*,
The
gene
produces
multiple
transcripts
with
alternative
5'
noncoding
sequences
;
t,
the
GC-rich
leader
sequence
also
contains
upstream
AUG
codon(s)
;
§,
translation
improves
upon
deleting
portions
of the leader
sequence
.
on July 10, 2011jcb.rupress.orgDownloaded from
Published November 15, 1991

adage
that
nothing
bad can happen
to a
rotten
eggplant
:
a
highly
structured
5'
sequence
is
so
inhibitory
to
translation
that
the further
slight
diminution
attributable
to
one
or
two
small
upstream
ORFs
should
hardly matter
.
A
more
interest-
ing
view
is
that
upstream
ORFs
(initiating
at
AUG
or
AUG-
cognate codons)
might
actually
be
necessary
to
mitigate
the
inhibitory
effects
of a
GC-rich
leader
sequence
.
The
argu-
ment
here
is
that
80S
ribosomes
engaged
in
translating
the
upstream
ORFs
might
be
able
to
penetrate
duplex
structures
that
are
too
stable
to
be
penetrated
by
scanning
40S
ribosomal
subunits-an
idea
which
is
supported
by
some
evi-
dence
from
experimental
constructs
(179,
195)
.
If
a
smatter-
ing
of upstream
initiator
codons
indeed
facilitates
the
trans-
lation
of
mRNAs
with
highly
structured leader
sequences,
they
probably
provide
only
a
small
measure
of
relief
.
The
major
experimental
finding
is
that
mRNAs
with
long,
GC-
rich
leader
sequences
are
translated
inefficiently
.
And
a
sur-
prising
number
of vertebrate
mRNAs
fit
that
bill
.
Coda
The
usually favorable
context
around
the
AUG
start
site
in
vertebrate
mRNAs
ensures
the
fidelity
of
initiation
.
Because
recognition
of
the
AUG
codon
is
a
late
event
in
the
initiation
process,
however,
a
good
context
should
not,
and
does
not
(194),
affect
the
ability
of
one
mRNA
to
outcompete
another
.
Translational
efficiency,
defined as
competitive
ability,
is
probably
determined
instead
by
accessibility
of
the
capped
5'
end
of
the
mRNA,
since
the
5'
end
constitutes
the
apparent
entry
site
for the
40S
ribosome/factor
complex
.
Effective
competition
for
the
40S
ribosome/factor
complex
is
not
sufficient,
however
;
translational
efficiency
(defined
now
as
actual
production
of
the
intended
protein)
can
still
be
re-
duced
by upstream
AUG
codons
or by
base-paired
structures
that
constitute
barriers
to the
scanning
40S
ribosome
.
The
particulars,
such
as
how
much
secondary
structure
is
re-
quired
to
inhibit
scanning,
and
the
available
evidence
are
summarized
elsewhere
(200)
.
If
one
accepts
the
general
no-
tion that
base-paired
structures
and
upstream
AUG
codons
can
block
ribosome
entry
and/or
scanning,
then
the
encum-
bered
leader
sequences described
herein
pose problems
.
Time
will
tell
which
of the
AUG-burdened
cDNA
se-
quences
described
above
represent
functional
mRNAs
and
which
represent
mRNA
precursors
.
The
likelihood
ofthe
lat-
ter
explanation
increases as the
number
of
upstream
AUG
codons
increases
:
cDNAs
with
a
dozen
or so
upstream
AUG
triplets
(45,
85,
140,
151a,
161,
256, 309,
315,
421)
almost
certainly
do
not represent
translatable
transcripts!
The
im-
portance
of
using
appropriate
primers
to
search
for
alterna-
tive
5'
noncoding
sequences
cannot
be overemphasized
.
Positioning a
primer near
the
5'
end
ofthe longest
cDNA
(85,
260)
will
nicely
pinpoint
the
start
site
of
the
longest
tran-
script,
but
alternative
mRNAs
with
shorter leader
sequences
inevitably
will
be
missed
unless
the
primer
is
positioned
close
to
the
AUG
initiator
codon
.
The
fact
that
so
many
AUG-burdened
5'-noncoding
sequences
have already
been
traced to retained introns
or
to
other
irregularities
(documented
above
and
in
reference
193)
encourages
the
view
that
many
of
the
cDNAs
in
Table
III
may
correspond
to
nonfunctional
transcripts rather
than
to
functional
mRNAs
.
On
the other
hand,
when
the correct
form
of the
mRNA
is
eventually
deduced,
genes
thereby eliminated
The
Journal
of
Cell
Biology,
Volume
115,
1991
from
Table
III
often
move
into
Table
IV!
One
way
or
another,
the
mRNAs
for
oncoproteins,
transcription
factors,
growth
factors,
etc
.,
seem
destined
to
be
translated
poorly
.
For
GC-burdened
cDNAs,
the solution of
switching
promoters
to
produce
an
alternative,
less
encumbered
5'
non-
coding
sequence
has
been
documented
in
only
a
few
cases
(178,
283,
317,
377)
.
Because
alternative
leader
sequences
can
easily
be
missed,
as
mentioned
above,
their
frequency
might
be
higher
than
presently
appears
.
Nevertheless,
be-
cause
of
the
consistency
with
which
GC-rich
leader
se-
quences
occur,
it
seems
farfetched
to
argue
that
most
of
those
cDNAs
(Table
IV)
derive
from
nonfunctional
transcripts
rather
than
from
functional
mRNAs
.
Unlike
the
tabulation
of
AUG-burdened
leader
sequences,
which
in
time
tends
to
be
whittled
down
by
corrections,
the
tabulation
of
GC-
burdened
leader
sequences keeps
growing
.
It
includes
mRNAs
for
many
cytoskeletal
and
housekeeping
proteins
in
addition to the
regulatory
proteins
mentioned
in
Table
IV
.
Thus,
it
seems
likely
that
some
(probably
many)
vertebrate
mRNAs
have
enough
secondary
structure
at
the
5'
end
to
throttle
translation
.
The
biggest
uncertainty
may
be
whether
these
mRNAs
invariably
are
translated
poorly
or
whether
their
translation
is
"derepressed"
in
response
to
mitogens,
for
example,
by
modifications
of
the
translational
machinery
or
induction
of
helicases
.
(Although
numerous
modifications
of
the
translational
machinery
correlate
with
a
serum-induced
increase
in
translation,
no
causal
connection has
yet
been
established
.)
The
widespread
occurrence
of
5'
noncoding
sequences
that
appear
unfavorable
for
translation
might
be
rationalized
by
the
ability
of
GC
motifs
to
promote
transcrip-
tion
.
In
some
vertebrate genes,
sequence
elements
located
downstream
from
the
cap
site
indeed
augment
the
yield of
mRNA
(51,
97,
131,
13
la,
163,
210,
327,
392)
.
Whatever
the explanation, the
encumbered
leader
se-
quences
described
herein represent
a
minority
of
the
ver-
tebrate
cDNA
sequences
that
have
been
analyzed,
and
they
are a
distinctly
nonrandom
set
.
AUG-burdened/GC-rich
leader
sequences
virtually
never
occur
on
mRNAs
that
en-
code
globins,
albumins,
caseins,
immunoglobulins,
his-
tones, or
other
highly
expressed
proteins
.
The
fact
that
genes
for
growth
factors,
cytokine
receptors,
proto-oncogenes,
etc
.,
often
produce
transcripts
with
encumbered
5'
noncod-
ing
sequences
suggests extensive
regulation
of the
regula-
tors,
at
the
level
of
translation
and/or
RNA
processing
.
Research
in
the
author's
laboratory
is
supported
by
the
National
Institutes
of Health
(grant
GM-33915)
.
This
paper
is
dedicated
to
Judith
Shakespeare
.
Received
for
publication
8
May
1991
and
in
revised
form
12
July 1991
.
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