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J Biol Chem, Vol. 273, Issue 48, 31629-31632, November 27, 1998
,From the Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-3945 and the § Department of Developmental Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel 991120
In 1989, shortly after the discovery of
CAAT/enhancer-binding protein
(C/EBP)1 and in a
period before it was clear that there was more than one form of C/EBP,
McKnight et al. (1) published a review entitled: "Is C/EBP
a Central Regulator of Energy Metabolism?" This prediction of a
critical metabolic role for this transcription factor was based on the
very slim evidence that C/EBP was involved in the transcription of a
number of metabolically important genes such as 422/aP2,
phosphoenolpyruvate carboxykinase (PEPCK), and fatty acid synthase, in
addition to its role in the differentiation of adipocytes (2, 3). Over
the decade since this article was published, the prediction has proven
to be remarkably accurate. C/EBP is now known to comprise a gene family
with a number of closely related members, the biology of which has been
detailed in the first minireview in this series by Lekstrom-Himes and
Xanthopoulos (4). These C/EBP isoforms can stimulate or inhibit
transcription from a growing list of genes in a variety of tissues in
animals as diverse as chickens and rats. One of the critical aspects of the biology of C/EBP that has emerged over the past 10 years is the key
role that members of the family of transcription factors play in both
the development and maintenance of metabolically important processes
(1, 5, 6). This review will focus on the effects of C/EBP isoforms on
the control of transcription of the gene for the key gluconeogenic
enzyme PEPCK (GTP) (EC 4.1.1.32) as a model for its regulation of other
genes that code for enzymes of metabolic importance.
The transcriptional control of the gene for the cytosolic form of
PEPCK from the rat (7-9) and chicken (10, 11) has been extensively
studied. The promoter regulatory region of the gene from the rat is
shown in Fig. 1. Because the sequence of
the promoter for the PEPCK gene from the mouse, rat, and human has been
remarkably conserved (greater than 95% sequence identity), it is
reasonable to assume that the pattern of transcriptional regulation
noted from studies with the PEPCK gene promoter from rodents is
characteristic of the control in most mammalian species. The PEPCK gene
promoter contains several critical regions of transcription factor
binding that are required for the regulation of PEPCK gene
transcription.
INTRODUCTION
Top
Introduction
References
Transcriptional Regulation of the PEPCK Gene Promoter
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Fig. 1.
Transcriptional regulatory elements of
the PEPCK promoter. The positions of regulatory elements in
the PEPCK gene promoter are represented by ovals, and the
various proteins that regulate transcription of the PEPCK gene are
shown relative to their binding sites on the promoter. The
abbreviations used are: TRE, thyroid hormone regulatory element; GRE,
glucocorticoid regulatory element; TBP, TATA-binding protein(s);
PPARRE, PPAR regulatory element; AF-1; accessory factor-1; DBP,
D-binding protein; GR, glucocorticoid receptor; RAR, retinoic acid
receptor; RXR, retinoic X receptor. This figure is taken from Ref.
37.
Region 1--
This region contains a cAMP regulatory element (CRE)
(
91 to 84), which is about 60 base pairs 5' from the TATA box (29 to 23) and is immediately adjacent to a nuclear factor 1 (NFI)-binding site (116 to 104). The CRE has been shown to bind
members of the leucine zipper family of transcription factors,
including C/EBP
(12, 13), C/EBP
(14), D-binding protein (15), AP-1 (16), cAMP regulatory element-binding protein (CREB) (17), cAMP
regulatory element modulator (CREM) (18), and Jun/Jun homodimers (16).
The CRE is required for the full induction of transcription from the
PEPCK gene promoter by cAMP (19). Recently, we have demonstrated that
NFI inhibits transcription from the PEPCK gene promoter and suggested
that an interaction between NFI and CREB-binding protein (CBP) is
involved in the control of the basal level of transcription of the
PEPCK gene in the liver (20).
Region 2--
This region contains an hepatic nuclear factor 1 (HNF-1) regulatory element (190 to 185), which, despite its name,
is critical for the expression of the PEPCK gene in the kidney of
transgenic mice. There is a C/EBP-binding domain (234 to 235),
termed P3(I), which is required for the liver-specific expression of
the PEPCK gene (21); members of the C/EBP family are the only
transcription factors that are known to bind to the P3(I) site. This
site is involved in the cAMP stimulation of transcription from the
PEPCK gene promoter since its deletion results in a 60-70% drop in
expression from the promoter in the presence of cAMP in both hepatoma
cells (19) and in transgenic mice (21). C/EBP also binds to the P4 site
(282 to 274) (12). A thyroid hormone regulatory element is located
at 332 to 316 of the PEPCK gene promoter (22, 23).
Region 3--
This region contains the glucocorticoid response
unit (GRU) composed of two glucocorticoid regulatory elements, three
accessory factor-binding sites, and a CRE (24). The entire element lies between 321 and 455 of the PEPCK gene promoter (24). The GRU also
contains an insulin regulatory element (IRE) (414 to 400), which
lies within the AF2 domain of the GRU (the AF2 site binds C/EBP and
HNF-3) and is responsible for about 50% of the inhibitory effect of
insulin on hepatic PEPCK gene transcription (25). However, deletion of
the IRE completely inhibits the diabetes-induced increase of PEPCK gene
transcription in the liver of transgenic mice and renders the PEPCK
gene promoter refractory to induction by glucocorticoids (26).
Region 4--
This region contains a PPAR
regulatory element
(999 to 987), which is required for the adipose tissue-specific
expression of the PEPCK gene in both cultured adipocytes (27) and in
adipose tissue of transgenic mice in which the region containing the
PPAR element has been deleted (28).
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The Role of C/EBP Isoforms in the Regulation of PEPCK Gene Transcription |
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Of the C/EBP isoforms, only C/EBP (6, 23, 29), C/EBP (14),
and D-binding protein (15) have been implicated in the control of PEPCK
gene transcription; all three of these isoforms of C/EBP bind to the
PEPCK gene promoter and can stimulate transcription from the promoter
when transfected into hepatoma cells. It is likely that these three
transcription factors, either individually or in combination, regulate
PEPCK gene transcription in the liver. Wang et al. (29)
partially resolved the issue of which isoform of C/EBP controls the
development of hepatic PEPCK gene transcription when they reported that
PEPCK and glucose 6-phosphatase mRNAs were absent in the livers of
mice with a deletion in the gene for C/EBP (C/EBP/ mice).
Subsequently, Flodby et al. (30) demonstrated that
C/EBP/ mice also have immature lung development. The complete
analysis of those genes whose expression is affected by a deletion in
the gene for C/EBP has not been performed to date, but it is clear
from the available data that a number of these genes are involved in
integrative metabolic functions (5). These proteins include enzymes
involved in gluconeogenesis, glycogen synthesis, and fatty acid
synthesis that are markedly altered in the absence of C/EBP. For
example, C/EBP/ mice have no hepatic glycogen at birth (there is
no detectable glycogen synthase in the liver), and in the absence of
PEPCK and glucose 6-phosphatase, they cannot synthesize glucose to
maintain glucose homeostasis in the perinatal period; both brown and
white adipose tissues also fail to develop normally (29).
The administration of dibutyryl cAMP to C/EBP/ mice at day 19 of
fetal life resulted in a blunted induction of PEPCK mRNA in the
liver (about 10% of the control value) but caused a marked increase in
the level of C/EBP mRNA in the livers of the C/EBP/ mice
(6). It is thus possible that C/EBP assumes the function of
regulating PEPCK gene transcription in the absence of C/EBP. The
temporal pattern of expression of the isoforms of C/EBP could be
critical for the programmed initiation of gene transcription in the
liver. In preliminary studies from our laboratory we have shown that
C/EBP//C/EBP+/ mice do not survive past day 18 of fetal
life,2 suggesting that the at
least one allele for C/EBP must be present in the mouse to ensure
that development proceeds.
The role of C/EBP in mediating cAMP-stimulated transcription of the
PEPCK gene was first demonstrated by Liu et al. (19). They
reported that a mutant PEPCK gene promoter, in which the CRE has been
replaced by the P3(I) site (which binds only C/EBP), is as responsive
to the catalytic subunit of PKA (PKAc) as the native PEPCK gene
promoter. Recently, Roesler et al. (31) demonstrated that
C/EBP (but not C/EBP) can substitute for CREB in cAMP-stimulated PEPCK gene transcription and mapped the C/EBP activation domain to a
region between amino acids 176 and 217. In addition, Roesler et
al. (32) also reported that a dominant repressor of C/EBP, when
transfected into hepatoma cells, significantly inhibited induction of
transcription from the PEPCK gene promoter by PKAc. Interestingly, the
DNA-binding domain of C/EBP was not required for its effect on PEPCK
gene transcription in hepatoma cells but was required in non-hepatoma
cells, suggesting that there is an interaction between C/EBP and other
factors, which are critical for the full effect of C/EBP on PEPCK
gene transcription.
A major problem in studying the long term effects of a deletion in the
gene for C/EBP in mice is the lethality of the deletion in the
perinatal period. Lee et al. (33) constructed a conditional knockout allele of C/EBP using the Cre/loxP recombinase
system. The Cre recombinase was delivered to the livers of adult mice containing the gene for C/EBP flanked by loxP sites,
using a recombinant adenoviral vector carrying the cre gene.
The hepatic expression of the genes for both C/EBP and PEPCK was
reduced by 90% in the livers of these mice, indicating that C/EBP
is required for maintaining the basal levels of PEPCK in the livers of
adult mice. It is surprising that this requirement for C/EBP could
not be compensated for by C/EBP or other C/EBP isoforms, which are
abundantly expressed in the liver of adult animals.
Mice homozygous for a deletion in the gene for C/EBP (C/EBP/
mice) were initially generated to study the effects of C/EBP on the
interleukin-6 signaling pathway. Screpanti et al. (34) reported that the mice developed a pathology similar to animals that
overexpress interleukin-6; they have splenomegaly, peripheral lymphadenopathy, enhanced hemopoiesis, and altered T-helper cell function. Despite these problems with the immune system, the mice had
no overt disruption of glucose homeostasis (34). However, both Screpanti et al. (34) and Tanaka et al. (35)
noted a failure to obtain the expected Mendelian ratio of mice
heterozygous for a deletion in the gene for C/EBP, although the
appropriate number of C/EBP/ mice was present at 20 days of
fetal life. In a recent study we reported that there are two phenotypes
noted with the C/EBP/ mice (6). Animals with phenotype A live until about 4-6 months of age and die of problems associated with a
severely compromised immune system, whereas the other half of the
C/EBP/ mice, those with phenotype B, die within the first hour
after birth of profound hypoglycemia.
Animals with the B phenotype have normal levels of hepatic glycogen but
do not mobilize this glycogen and do not initiate hepatic PEPCK gene
transcription, which is characteristic of the neonatal period (36).
However, PEPCK gene transcription and glycogen mobilization from the
liver can be induced during the perinatal period in C/EBP/ mice
by the administration of dibutyryl cAMP.2 It is possible
that C/EBP/ mice are less responsive to cAMP and are thus not
able to maintain the level of glucose in the blood by either
glycogenolysis or gluconeogenesis. C/EBP/ mice have about 25%
of the total hepatic cAMP, and the administered dose of glucagon to
adult C/EBP/ mice (A phenotype) does not cause the same level of
increase in the concentration of cAMP as with C/EBP+/+
mice.3 C/EBP/ mice (A
phenotype) also have a diminished ability of the liver and adipose
tissue to respond to glucagon and epinephrine administration.3 The rate of glucose production by the
liver after glucagon administration is less than control mice, and the
rate of free fatty acid release from adipose tissue in vitro
after the addition of epinephrine is greatly reduced. It thus seems
likely that the inability of C/EBP/ mice with the B phenotype
(mice die immediately after birth) to maintain the appropriate level of
hepatic cAMP is responsible for the failure of these animals to
initiate glucose homeostasis at birth. We are currently investigating
the mechanism(s) responsible for the lower level of cAMP in the livers
of these mice.
C/EBP/ mice (A phenotype) also are less responsive to
administered glucocorticoids.2 Dexamethasone induces
transcription of the gene for PEPCK in the kidney of C/EBP/ mice
(A phenotype) to about 10% of the level noted in control mice. There
is, however, no defect in the cAMP induction of PEPCK gene
transcription, indicating that C/EBP, although critical for the full
response of metabolically important genes to hormones such as
glucocorticoids, glucagon, and epinephrine, is not required for the
induction of PEPCK by cAMP.
The reason there are two different phenotypes noted with the
C/EBP/ mice is not clear. We assume that there are factors produced in the mice with phenotype A that allows them to transcribe genes critical for survival during the perinatal period. These "modifier genes" are expressed as a result of the genetic
background of the mice, which are not inbred. This possibility is
supported by preliminary experiments in which mice homozygous for a
deletion the gene for C/EBP were backcrossed with C57/BL6 mice; no
C/EBP/ offspring from these matings survived after
birth.4 One simple
explanation for this result is that the gene(s) for other C/EBP
isoforms are up-regulated in mice with the A phenotype, permitting
their survival through the perinatal period. However, there is no
apparent up-regulation in the expression of the gene for C/EBP or
C/EBP
4 in the livers of the C/EBP/ mice; the
level of expression of the genes for the other members of the C/EBP
family has not as yet been investigated in detail in these mice.
| |
Mechanism of the Effect of C/EBP on PEPCK Gene Transcription; Interaction with CBP/p300 |
|---|
C/EBP isoforms bind to three major sites on the PEPCK gene promoter, the CRE, the P3(I) site, and the AF2 element; all three are critical for the regulated transcription of the PEPCK gene in the liver. A deletion in the CRE or the P3(I) site results in 70% loss of transcriptional induction from the PEPCK gene promoter by cAMP, whereas mutating both sites virtually eliminates the inductive effects of the cyclic nucleotide (19). In addition, mice containing a transgene with the PEPCK gene promoter lacking the P3(I) site (only isoforms of C/EBP are known to bind to this site) have a greatly diminished level of expression of the transgene in the liver (21). A deletion in the AF2 site in the PEPCK gene promoter eliminates the stimulatory effect of diabetes on transcription from that promoter when it is introduced into transgenic mice.5 The results of gene deletion studies outlined above offer further support for the importance of C/EBP isoforms in both the liver-specific expression of the PEPCK gene and the cAMP-regulated transcription from the PEPCK promoter. The mechanism by which C/EBP regulates transcription from the PEPCK gene promoter remains to be determined. There are, however, a number of recent research studies, and work in our own laboratory now sheds some light on this critical question.
C/EBP isoforms have been shown to bind to the dyad-symmetric sequence
ATTGCGCAAT (38). The sequences for the CRE and the P3(I) sites in the
PEPCK gene promoter are not identical to this consensus sequence, which
is consistent with the varying affinity of C/EBP for different gene
promoters. Phosphorylation of C/EBP by protein kinase C (PKC)
results in an attenuation of its binding to DNA (39, 40). PKC inhibits
transcription from the PEPCK gene promoter in hepatoma cells (41),
suggesting a connection between C/EBP and the signaling pathways
involved in the cellular effect of PKC on the PEPCK gene.
The various isoforms of C/EBP have been shown to bind to a number of
other transcription factors (42) and also can interact with the
glucocorticoid receptor to regulate gene transcription (43). For
example, both C/EBP and C/EBP form a heterodimeric complex with
ATF-2, a transcription factor that binds to the CRE of a number of gene
promoters and activates transcription (42). C/EBP diminishes the
inductive effect of ATF-2 on transcription from a hybrid promoter,
containing the thymidine kinase minimal promoter and a C/EBP-binding
site, when expression vectors with genes coding for both proteins are
transfected into Fao hepatoma cells; this supports a functional
interaction of C/EBP and ATF-2. Recently, Mink et al.
(44) reported that the transcriptional co-activator CBP binds C/EBP
at a region from amino acids 1752 to 1859 of CBP and that this domain,
when transfected into cells in culture, was a dominant-negative
inhibitor of C/EBP-induced transcription. CPB can stimulate the
synergy between C/EBP and the transcription factor Myb for binding
to a minimal promoter-containing binding sites for both transcription
factors. The amino-terminal region of C/EBP binds to CBP; this
region contains several stretches of amino acids that are conserved in
the various isoforms of C/EBP, suggesting that other members of the
C/EBP family of transcription factors bind to CBP via this site.
CBP/p300 is the designation of a group of co-activator proteins of
which CBP and p300 are the prototypes (45, 46). CBP and p300 are highly
related proteins, with 75% similarity and 63% sequence identity
across the entire length of the protein (see Ref. 47 for a review). CBP
from the mouse is composed of 2440 amino acids; the genes for both CBP
and p300 in this species have been deleted by homologous recombination
(48). Mice homozygous for a deletion in the gene for p300 (p300/
mice) die between embryonic days 9 and 11, exhibiting defects in
neurulation, cell proliferation, and heart development (48).
Interestingly, mice that are heterozygous for a deletion in the gene
for p300 also show increased lethality, whereas mice that are
heterozygous for a deletion in genes for both CBP and p300
die as embryos (48). Not all of the functions of CBP and p300 are
similar; fibroblasts prepared from p300/ mice (normal CBP) were
defective in their response to retinoic acid but responded normally to
CREB (48). These results strongly support the critical role of both CBP
and p300 in mammalian cell proliferation and development.
CBP/p300 has a number of discrete functions in regulating gene
transcription. It binds to RNA polymerase II and can integrate regulatory signals from transcription factors and chromatin by virtue
of its intrinsic acetyltransferase activity (49). CBP/p300 can itself
be phosphorylated on serine and threonine residues during retinoic
acid-induced differentiation of F9 embryonal carcinoma cells (50),
suggesting that phosphorylation of the protein by a
cyclin-dependent kinase can control its transcriptional
activity. At the present time there are more than 30 proteins known to
bind to CBP/p300, and the list is growing (47). Nakajima et
al. (51) have suggested a model in which CREB is phosphorylated by
PKA and then binds to CBP, resulting in an association of CBP with TFIIB and RNA polymerase II. Because isoforms of C/EBP can also bind to
CBP (but at a different location), it is reasonable to assume that they
act in the same manner in controlling the transcription of a subset of
cAMP-responsive genes such as PEPCK, acetyl-CoA carboxylase, and
glucose-6-phosphatase. These genes are expressed at high levels in the
liver, where the concentration of C/EBP is highest and the level of
CREB is relatively low. However, there are no data indicating that PKA
phosphorylation of C/EBP results in activation of transcription so
that some mechanism involving the direct phosphorylation of CBP may be
responsible for induction of PEPCK gene transcription by cAMP.
The CRE of the PEPCK promoter lies immediately adjacent to an
NFI-binding domain (12), and NFI inhibits the induction of transcription from the PEPCK gene promoter by PKAc (20). However, it
has been demonstrated in gene transfection studies that the NFI-binding
site of the PEPCK gene promoter is not required for the effect of NFI.
This suggests that there is an interaction between NFI and another
protein(s), neither of which need to bind to the PEPCK gene promoter to
form a productive complex. Recently, Leahy et
al.6 provided evidence
that this interaction is with CBP, because co-transfection of CBP with
NFI overcomes the strong negative effect of NFI on transcription from
the PEPCK gene promoter. This effect is
concentration-dependent for both CBP and NFI. Preliminary data suggest that NFI binds to the CREB-binding domain of CBP. In
support of the role of CBP in the regulation of PEPCK gene transcription is our observation that E1A, the adenoviral early protein, strongly inhibits cAMP-induced transcription from the PEPCK
gene promoter (52).6 Because E1A binding to CBP/p300 is
well characterized as a major mechanism by which adenovirus controls
host cell function, it is likely that CBP/p300 is also a critical
factor in the transcriptional response of PEPCK to hormones (see Fig.
2).
| |
Model for the Control of PEPCK Gene Transcription |
|---|
Our current model (Fig. 2) for the
role of C/EBP isoforms in the control of PEPCK gene transcription is
from Leahy et al.6 and shows the PEPCK gene
promoter arranged to stress the role of CBP in coordinating the
transcriptional response of cAMP, glucocorticoids, and insulin. C/EBP,
which binds to both the CRE and the P3(I) site of the PEPCK gene
promoter, interacts with CBP, probably in response to stimulation by
PKA. The effect of glucocorticoids on PEPCK gene transcription is also
exerted via the interaction of the glucocorticoid receptor with its
well characterized binding site on CBP. It is also likely that insulin
exerts its effect on PEPCK gene transcription by interfering with this
interaction. The removal of the AF2 domain in the PEPCK gene promoter
results in a total loss of transcriptional induction from the promoter in livers from diabetic mice.4 Although the glucocorticoid
receptor does not bind to the AF2 region of the PEPCK gene promoter
(24) it may exert its effect on transcription via an interaction with
CBP. Other hormonal effectors of PEPCK gene transcription, such as the
thyroid hormone receptor or the retinoic acid receptor, also are known
to bind to CBP at well characterized sites (47) and most likely
influence PEPCK gene transcription via that mechanism. Finally, NFI
interacts with CBP to maintain PEPCK gene transcription in the liver at a low basal level in the absence of PKA-mediated phosphorylation of
either C/EBP or CBP.6 The mechanism by which
phosphorylation of either or both of these proteins alters
transcription of the PEPCK gene remains to be determined.
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ACKNOWLEDGEMENT |
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We thank Dr. Martin Snider for critically reading the manuscript before publication.
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FOOTNOTES |
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* This minireview will be reprinted in the 1998 Minireview Compendium, which will be available in December, 1998. This is the fifth article of five in the "Biological Role of the Isoforms of C/EBP Minireview Series." This work was supported by Grant DK-22541 from the National Institutes of Health and by Grant 96117 from the United States-Israel Binational Foundation.
Trainee of the Metabolism Training Program of the National
Institutes of Health (Grant DK-07139).
¶ To whom correspondence should be addressed. Tel.: 216-368-5302; Fax: 216-368-4544; E-mail: rwh{at}po.cwru.edu.
The abbreviations used are: C/EBP, CAAT/enhancer-binding protein; PEPCK, phosphoenolpyruvate carboxykinase; CRE, cAMP regulatory element; NFI, nuclear factor I; CREB, cAMP regulatory element-binding protein; CBP, CREB-binding protein; GRU, glucocorticoid response unit; HNF-1, hepatic nuclear factor I; IRE, insulin regulatory element; PPAR, peroxisome proliferator-activated receptor; PKAc, catalytic subunit of PKA; PKC, protein kinase C.
2 C. Croniger and R. W. Hanson, unpublished results.
3 S. Liu, C. Croniger, J. Ren, M. Shiba, V. Poli, R. W. Hanson, and J. E. Freedman, submitted for publication.
4 V. Poli, unpublished observations.
5 P. S. Lechner, C. Croniger, and R. W. Hanson, unpublished observations.
6 P. Leahy, D. R. Crawford, G. Grossman, A. Chaudhry, R. Gronostajski, and R. W. Hanson, submitted for publication.
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 Y. Shi, S. I. Taylor, S.-L. Tan, and N. Sonenberg When Translation Meets Metabolism: Multiple Links to Diabetes Endocr. Rev., February 1, 2003; 24(1): 91 - 101. [Abstract] [Full Text] [PDF]
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M. Young Lee, C.-H. Jung, K. Lee, Y. Hyun Choi, S. Hong, and J. Cheong Activating Transcription Factor-2 Mediates Transcriptional Regulation of Gluconeogenic Gene PEPCK by Retinoic Acid Diabetes, December 1, 2002; 51(12): 3400 - 3407. [Abstract] [Full Text] [PDF]
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 E. Feifel, P. Obexer, M. Andratsch, S. Euler, L. Taylor, A. Tang, Y. Wei, H. Schramek, N. P. Curthoys, and G. Gstraunthaler p38 MAPK mediates acid-induced transcription of PEPCK in LLC-PK1-FBPase+ cells Am J Physiol Renal Physiol, October 1, 2002; 283(4): F678 - F688. [Abstract] [Full Text] [PDF]
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T. N. Cassel, T. Berg, G. Suske, and M. Nord Synergistic Transactivation of the Differentiation-dependent Lung Gene Clara Cell Secretory Protein (Secretoglobin 1a1) by the Basic Region Leucine Zipper Factor CCAAT/Enhancer-binding Protein alpha and the Homeodomain Factor Nkx2.1/Thyroid Transcription Factor-1 J. Biol. Chem., September 27, 2002; 277(40): 36970 - 36977. [Abstract] [Full Text] [PDF]
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L. A. Jurado, S. Song, W. J. Roesler, and E. A. Park Conserved Amino Acids within CCAAT Enhancer-binding Proteins (C/EBPalpha and beta ) Regulate Phosphoenolpyruvate Carboxykinase (PEPCK) Gene Expression J. Biol. Chem., July 26, 2002; 277(31): 27606 - 27612. [Abstract] [Full Text] [PDF]
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A. E. Allen-Jennings, M. G. Hartman, G. J. Kociba, and T. Hai The Roles of ATF3 in Liver Dysfunction and the Regulation of Phosphoenolpyruvate Carboxykinase Gene Expression J. Biol. Chem., May 24, 2002; 277(22): 20020 - 20025. [Abstract] [Full Text] [PDF]
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 M. NORD, T. N. CASSEL, H. BRAUN, and G. SUSKE Regulation of the Clara Cell Secretory Protein/Uteroglobin Promoter in Lung Ann. N.Y. Acad. Sci., December 1, 2000; 923(1): 154 - 165. [Abstract] [Full Text] [PDF]
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