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R
e sp
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a ct
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E
-E
st
r og
e nR
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o n s eEle
m
e nt
Et
s -E
-t w
e nt y
six
E 2 F
-[
T
r a n s c ri
p
t io n
Fa c
t
o rf
am i
l
y
n am
e;
n ot
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t
io n
]
Fo x
A
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Fo x
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le
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G
A T A
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li
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d
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ep
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E
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h
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em
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IS R E
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St
im
ul
at io n
R
e sp
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l
em
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LX R
E
(
D R 4
/
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R
)
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iv e r
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p
t
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m
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R E
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et
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T
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elt
a -M
et
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nD
el
ta
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-[
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M
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9
-[
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n ot
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r e via
t io n
]
M
6 1
-[
N
am
e;
n ot
a n ab b
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t io n
]
N F
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u c
l
e a rF
a cto r
k
ap p
a-lig h
t
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h
ai
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h
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t
ed
B
c ell
sN F l
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u cl
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a ct
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-N
u cl
e a rR
e sp i
r at
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F
a ct
o r1
O
ct
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ct
am
e r-B i
nd
i
ng T
r a n s c ri p t
io n
F
a ct
o rP
a x -P
air e
d
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o xP B R E
M
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e n ob
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nh
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R E
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r oi if
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o rH
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p
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m
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E
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r e
g
n a n eX R
e sp
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m
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-T
um
o rP
r ot
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5
3
RA
RE
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et i
n oic
A
cid
Re s
p
o n s eE
l
em
e nt
R
O RE
-R
e
t
i
n oid
-r e
la
t
ed O
rp h
a nRe c e
p
t
o rRe s
p
o n s eE
le
m
e nt
sS O X
-S
ry
-r el
at
ed
H
i
g
h
-M
ob
il
it y G
r o up
Bo x
S
P l
-S p
e cif
i
ci t
y
P
r ot
ein
1
S R E P B
-S t
e r ol
R
eg
ula
t
o ry
E
le
m
e nt B i
nd i
ng
P
r ot
ei
nST
A T
-S
i g
n al
T
r a n sd
u c e r s a nd
A
ct iv a
to r s o
f
T
r a n s c ri
p
t io n
T A
-[
N
u cle o
t i
de
Re
p
e at
]
T A L
-T
r a n s c ri
p
t io n
A
ct
iv a
t
o r-l i ke
Ef f
e ct
o rT CF
/ p
-c at
e ni
n -T
r a n s c ri p
t
i
o nF
a ct
o rp
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i
nT
G
F
p
-T
r a n sf
o rm
in
g G
r ow
t
h
F
a cto r
3
V D
RE
-V it
a
m i
nD R
e sp
o n s eEle
m
e nt
X
b p
l
-X
-b
o xb i
nd
in
C H A P T E R 1
In
t
r od
u ct io n
T
h
e r e a r e a n e st im
at
ed
3 0 0 0 T F
s c od
ed
in
t
li e
h
um
a ng
e n om
e(
8 %
of
t
h
e o rg
anis
m
st
ot
al
e n c od
ed
p
r ot
ei
n s)
e a ch
w it
h
t
he a
b
il
it y t
o a ct iv a
t
e o r s up p
r e s st
r a n s c ri
p
t io n o
f
ap
a rt ic u
la r
g
e n e(
s)
B
e c au s e of
t
h
ei
r ab
i
lit
y
t
o r eg
ula
t
et
r a n s c ri
p
t
io n
b
a s ed
o n c ell
ul
a r st
i
m
uli
(
eg
x e n ob i
ot
i
c e xp
o s u r e)
, u nd
e r st
a nd i
ng
T F
a c
t iv
i t y i
s a s ub
j
e ct
of
c o nsid
e r ab l
ein
t
e r e st
.[
1
]
A
s s u ch,
m
a ny T F
sh
a v eb
e e nw
el
l
cha r a c
t
eriz e
d b y
t
h
ei
rf
u n ct
io n s a n
d
i
nt
e r a ct io n s a s
w
el l
a st
h
ei
r r ole s
i
n o rg
a niz e
d
r eg
ul
at
o ry
n et w
o rk
s.T
he s e n e
t
w
o rks a r e
i
m
p
o rt
a nt t
o u nd
e r st
a nd in
g h
ow
a n org
a nis
m
r eg
ula
t
e sf
u n ct io n a n
d
c op
e sw it
h
e xp
o s u r eBe c a u s e o
f
t
h
ea
b
il
it y
of
T Fs
t
o r e sp
o nd
t
o xe n ob
io
t ic s
,t
h
el
iv
e ris a
m
aj
o r o rg
a n of
i
nt
e r e st
:it i
st
h
ep
rim
a ry
sit
ef
o rm
et
ab
olis
m
, r e sp
o n si b le
f
o rb
ot
h
x e n ob io
t
i
c a nd
n ut
rie n
t
m
et
ab
oli
sm d
u et
oit
s ab
u nd
a n c e of p h
a s el
/
l l
m
et
ab
olic e n z
y m
e s.[
2
]
P
ri
o rw
o rk h
a s sh
ow
nt
h
at
r eg
ula
t
o ry
i
nt
e r a ct
io n s a r e c o n s e r v e
d
t
o v a ry
i
ng d
eg
r e e si
n clo s e
ly
r e
la
te
d
o rg
a nis
m
s[
1
,3
]
H
ow
e v e r,T F
a ct iv
it
y h
a s n ot y
et
b
e e nm
e a s u r ed
a c r o s sm
ult i
p
le
i
nd
iv
id
u als o
f
in
b
r ed
m ic e s
t
r ai
n sG
iv e n
t
he
ir
g
e n et ic s
im
i
la r
it y
,in
d
iv
i
d
u als
f
r om
a si
ng l
ei
nb
r ed
st
r ain
w
e r e e xp
e ct
ed
t
os
h
ow
h
i
g h ly
si
m
il
a rT F
a ct iv
it
y l
e v els
.I
n ad d it
io n
, v a ri
at i
o n am
o ng
st
r ai
n sw
a s e xp
e ct
ed
t
ob
e si
g
nif
ic a n
t
.W
i
t
h
t
h
em
et
h
od
olo
g y d
e vis e
d b y
R
om
a n o v et
al it
is n o
w
f
e a si b le
t
o a c c u r at
ely m
e a s u r e a ct
iv
it
y l
e v els o
f
m
ul
t i p
le
T Fs
[
4
]
A p p
lic a
t i
o n of
t
h
ep
la s
m id
r ep
o rt
e r sy
st
em w
i
ll
allo
w
d
et
e rm
in a
t io n o
f
t
h
ein
h
e r e nt
in
t
e r st
r ai
n va ria
bi
lit
y
of b
a s al
T F
a ct iv
it y
a c r o s sm
ult i
p l
e, sim
ult
a n e o u sl
y
m
e a s u r ed
T F
sin
t
h
em
o u s eliv e r
u s
in
g
ap
a n el
of i
nb
r ed
st
r ain s
.B
e c a u s et
h
em
e a s u r em
e nt
s a r em
ad
ein
-v
i
v ot
h
ey
c a n a c c o u nt
f
o rm
o r ec o
m p l
e xT
F
-T F
i
nt
e r a ct
io n s
w h ic
h m
ay
n ot
b
e ob
s e r v ab le
i
n c ult
u r ed
c el l li
n e s a sw ho
l
e o rg
a nis
m
in
t
e r a ct
io n s a r e
m
u ch m
o r e c om
p l
e xt
h
a nis o
la
t
ed
c el ls a n
d
/
o rt
is s u e
.El
u cid
at
in
g
t
h
e s e a ct
iv
it
ie s
w
il l
p
r o vid
e am
u ch
cle a r e r
p
ic
t
u r e of
t
he c o
m p l
e x r eg
ula
t
o ry
a nd
r e sp
o n siv e
i
nt
e r a ct io n s o
f
T F
s.O
u rh y p
ot
he s
i
sw
a st
h
at
, am
o ng i
nb
r ed
st
r ai
n s, r eg
a rd
i
ng
T F
a ct iv
it
y
,in
t
e r st
r ai
n v a ria
t io n
w
o uld
in
t
r a st
r ai
n c o r r ela
t io n
f
o r e a ch
st
r ai
n a nd w
h
et h
e rit w
a sfe a s
i
b l
et
o c o n st
r u ct
d if fe r e n
t
ia
b l
eT F
a ct
i
vi
t y
p
r of
il
e sfo r e a c
h
st
r ain
.F
u rt
h
e r,w
ew
e r ei
nt
e r e st
ed
in
t h
e ut il it y
of
t h
em
et h
od
t
o r et
u r nd
at
aw
h
ic
h
c o u
l d b
e u s ed in
t
h
ed is c o v e r
y
of y
et
d
e s c rib
ed
, c o op
e r at
iv e
T F
-
T F
a nd
T F
-g
e n ein
t
e r a ct
io n s
.W
e ap p li
ed
t
h
eh
i
g h
t
h
r o ug h p
ut
p l
a sm
i
d
r ep
o rt
e r sy
ste
m d
e v el
op
ed b y
Ro
m
a n o v et
al
[
4
]
t
o2
0
s
t
r ai
n s of
i
nb
r ed
m i
c et
op
r o c u r eI
n-v
i
voT F
a ct i
vit y
le v e
ls
.H
e r e,w
e sho
w
t
ha
t
s ai
d is
f
u n ct
io n a
l l
y
r ob
u st
w he n a
p p l i
ed
t
oi
n viv o
m
o u s e e xp
e ri
m
e nt
s.O
u r r e s ult
s sh
ow
ed
t
h
at
in
t
r a st
r ai
nT F
a ct iv
it
y
v a ria
t
io n
is
fa
ir
ly l
ow
w h
i
le
t
h
e r ei
s sig
nif i
c a nt
in
t
e r st
r ai
n v a ri
at
io n o
f
T F
a ct i
vit
y
a c r o s st
h
em
o u s ep
a n el
.F
r om t
h
ed
at
a,w
ew
e r e ab le
to
b
uil d T
F
a ct i
vit
y p
r of ile s
f
o r e a ch
st
r ai
n a sw
el l
a s c o r r ela
t
eT F
a ct iv
it
y
t
og
e n ee x
p
r e s sio n
.O
u r r e s ult
s a r ew
ell
r ep
r e s e nta
t iv e o
f k
n ow
nT F
-
T F
r ela
t io n s
h
i
p
sw h
i
le a
ls o s u
g g
e st
in
g
n o v el
T
F
-T F
in
t
e r a ct io n s
.
Fu r
t
h
e r, s u ch i
nfo r
m
at io n
w il l
c o nt
ri b
ut
et
oi
nt
ell ig
e nt
st
r ai
n s ele c
t io n a n
d p
r o vid
eC H A P T E R
2
L it
e r at
u r eR
e vie
w
T
r a n s c ri
p t
io n
f
a ct
o r s(
T F
)
a r e s eq
u e n c e sp
e cif
i
cD N A
b i
nd i
ng p
r ot
ei
n s r e sp
o n si
b le
fo r r e
g
ula
t
i
ng
g
e n et
ran s c rip t i
on[
5
]
,t h
e r eb y
d
e n ot i
ng
r e sp
o n si
b
i
l
it y
f
o rm
ain
t
ai
ni
ng h
om
e o st
a si
s a nd
st i m
ul
u s r e sp
o n s e.In o r
d
e rt
o r eg
ula
t
et
h
e v a st
q
u a nt it y
of f
u n ct
io n s a n
d g
e n e s,T
F
sh
a v em
ult
i
p
le
m
od
e s of
op
e r at io n a n
d
c a n
f
u n ct io n
in
d
ep
e nd
e nt
ly
o rw it
h in a c o
m
p l
e x of
ot
h
e rT F
st
h
r o ug h
eit
h
e rp
r om
ot
i
ng
o rp
r e v e nt i
ng
t
r a n s c rip
t
io n o
f
t
h
e c o rre sp
o nd
i
ng g
e n e.[
6
]
M
aj
o rhe
p
at
ic
f
u n ct io n s r e
g
ula
t
ed b
y
s ele c
t
ed
T F
a ct
iv
it
y
i
n cl
ud
e c ell p
r olife r a
t io n
, o xid
at iv e
s
t
r e s s,in
f la
m
m
at
io n
, a nd m
et
ab
oli
sm
W
it
h
o ut t
h
ep
r e cis e
r eg
ula
t
io n a n
d m
ed
i
ate
d
r e sp
o n s et
o r ele v a n
t
s
t
i m
ul i p
r o vid
ed b y T F
s s u ch f
u n ct
io n s c o u
ld
n ot
op
e r at
e a s sp
e cif
ic a
ll
y
o r a c c u r at
ely
a st
he
y d
o.T
h
e s ep
at
h w
ay
s a r ed i
s c u s s ed b
elo
w
r eg
a rd i
ng
t
he
i
rm
ole c u
la r
f
u n ct
io n
in
liv e r
t
is s u e a n
d
t
h
ei m p
o rt
a n c e of T Fs
i
nt
he
i
rp
e rf
o rm
a n c e.C
ell
P
r ol
i
f
e r at i
o nC
ell p
r olife r a
t
io n
is
t
he
i
n c r e a s e of
t
h
e n um
b
e r of
c ells
w
it
h
i
nt h
e c o nt
e xt
of
t
is s u e
g
r ow t
h
.A
st h
ep
rim
a ry
sit
ef
o r x e n ob
io
t ic
m
eta
b
olis
m
,t
he
l iv e r
is c o n s
t
a nt
ly
e xp
o s ed
t
op
ot
e nt ia
lly h
a rm
f
ul
s ub
st
an c e sw
h ic
h
c a n c a u s e c el lu
la r
d
am
ag
e a nd
/
o rd
e at
h
.T
he r e
f
o r e,
it i
s n e c e s s a ry
fo r
t
h
e c el ls o
f
s ai
d
t is s u e
t
obe
e
q
ui p p
ed w it
h
r eg
e n e r at
iv e c a
p
a ci
t y
.H
ep
at
ic
t
i
s s u eh
a s ap
a rt
i
c ul
a rly h i g h
ab il it
y
t
og
r ow
a nd
r eg
e n e r at
e,b
ot
h
n at
u r al l
y
a nd i
n r e sp
o n s et
op hy
sic a
l
o r ch
em
ic a
l d
am
ag
e.M
e
d i
at i
ng
p
r ol
ife r a
t io n
r eq
ui
r e s c o nt
r ol
o v e r
t
he c e
l l
cy
cle
w h i
ch i
s n ot
o nly m
ed ia
t
ed by
o rg
a n-s
p
e cif ic
T Fs
b
ut
als o
is
d
ep
e nd
e nt
o nt
h
e st
ag
e of
d
e v elo
p m
e nt
.!
?
]
D
u rin
g
em
b
ry
o nic a n
d p
o st
n at
al g
r ow t
h,
h
ep
at
o cy
te
di
f f
e r e nt ia
t io n
is r e
g
ula
t
ed b
y H N F l
a,N H F 4
a,F
o x a2
, a nd
Fo x a
3
.T
he s e
m
a st
e r r eg
ul
at
o ry f
a ct
o r sm
ai
nt
ain a
p
r e s e n c ei
nd
if f
e r e nt i
ate
d
c ell
s,by
a n et
w
o rk
of
T F
s r eg
ul
at
ed b
y
F 0 X
-M
-1
-B
.
[
7
]
In
m i
c e, aF O X
-
M
-1
-B k
n o c
k
o ut i
s em
b
ry
o ni
cle
t h
al
d
u et
od
im i
ni
sh
ed
D N
A
r ep l
i
c at
io n a n
d
in a
b i li
t y t
o e nt
e rm it
o sis
(
a7
5 %
r ed
u ct i
o nin
h
ep
at
ob la s
t
sw
a s obs e r v e
d
p
rio r
t
od
e at
h
) [
8
]
Fo
l lo
w
i
ng i
nj
u ry
.T
um
o rG
r ow
t
h
F
a ct
o r a(
T
G
F
a)
,T
um
o rN
e c r o sis
Fa c
t
or a(
T N F
a)
,l
nt
e rle u
k
in
-6
(
I
L
-6
)
, a nd h
ep
at
o cy
t
eg
r ow t
h fa c
t
o r(
H
G
F
)
i
nd
u c ep
r ol
ife r a
t io n v
i
a r e e nt
ry
of
t
e rm i
n al l
y
d
if fe r e n
t i
at
ed h
ep
at
o cy
t
e si
nt
ot
ot
h
e c el l
cy
cle
.[
9
-
1 1
]
W
it
h
o ut I L
-6
,im m
ed
i
at
ein
d
u ct io n o
f
t
h
e n e c e s s a ry
T Fs
(
N F
-k B
,A P
-
l
(
c-
F
o s
/
c-Ju n
)
,
St
at
3
, c -M y
c, a n
d
t
h
eC
/
E
B
P
|
3 f
am ily
)
f
ails
, r e s ult
in
g i
n ad
e c r e a s ei
np
r olif
e r at
io n
.[
1
2
,1 3
]
A
de c r e a s e
in
t
h
ef
u n ct i
o n al
m
a s s of
t
h
eliv e r
d
u et
o ato x
i
ci
n s ult
w
o uld d
e c r e a s et
h
em
et
ab
oli
c r at
e of
t
h
el iv e r
t
h
e r eb y
c om p
r om
is
in
g
it
s ab
il it
y
t
of
u n ct
io n
O
xid
ati
v eS
t
r e s sO
xid
at
iv e s
t
r e s sis a n
im b
ala n c e
b
et
w
e e np
r o-o xid
a nt
p
r od
u ct io n a n
d
t
he
r e s ult i
ng d
am
ag
e a nd
t
h
e ab il
it
y
of
t
h
e o rg
a nis
m
t
od
et
o xi
f y
t
he
p
r o-o xid
a nts a n
d
r ep
air a n
y d
am
ag
e.Pr o
-o x
id
a nt
s a r ec o
m
m
o nl y
r ef
e r r ed
to
a s r e a ct
iv e o
xy
g
e n sp
e ci
e s(
RO S
)
a nd
c a n o ri
g i
n at
efr o
m b
ot
h
e xt
e r n al
t
o a nd
in
t
e r n al
to
a n o rg
a nis
m
.P
rim
a ry
E
nd
og
e n o u s s o u r c e s of
R
O S
i
n cl
ud
e e nd
op l
a sm
ic r e
t
ic u
lu
m
(
f l
a v op
r ot
ein s
,CY P
e n zy m
e s)
,ly
s o s om
e s(
m y
el
op
e r o xi d
a s e)
,p
e r o xis o
m
e s(
o xid
a s e s,f la v o
p
r ot
ei
n s)
, a nd
m
i t
o cho n
d
ria
(
ele c
t
r o n ch
ai
np
r ot
ei
n c om
p
le x e s
)
.M
it
o ch
o nd
ria a r e
t
he s
in
g
le
la r
g
e st
s o u r c e of
e n
do
g
e n o u sR
O S
.A
st
he
p
rim
a ry
sit
e of m
et
abo
li
sm
t
he
liv e r r e
q
uir e s c o n s
id
e r ab le e n e r
g y
a nd
t
h
u sh ig h
n u
m b
e r of m
it
o cho n
d
ria
O
t
h
e r s o u r c e s of
R
O S i
n cl
ud
e x e n ob io
t
ic
m
et
abo
l is
m
,in
j
u ry
, a nd
e xt
e r n al
c a u s e ss u c
h
a she a
t
[
1 4
-1 6
]
H
ep
at ic
t
is s u e c a n
t
ole r a
t
em i
ld
o xid
at iv e s
t
r e s sd
u eto s u
f f ic
ie n
t
a nt io x
id
a nt
p
r e s e n c e.D
am
ag
eo c c u r s
w
he n
t
h
e o xid
a nt
-a n
t
io x
id
a nt
im b
ala n c e
b
e c om
e st
o o s e v e r ef
o rt
he
a nt i
o xid
a nt
d
efe n s e
m
e ch
a nis
m
st
o c op
e.[
1 4
]
R O S
c a n c a u s e c el l
ul
a rd
am
ag
ein
t w
ow
ay
s :p h y
sic a
l d
am
ag
et
ot
he c e
l l
a nd
a
