1 Gastroenterology Research Unit, 2 Department of Molecular Neurosciences, and 3 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55901
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ABSTRACT |
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The
control of epithelial cell proliferation, differentiation, and
apoptosis requires a balance between signaling and transcriptional regulation. Recent developments in pancreatic cell research have revealed that transforming growth factor- (TGF-
) signaling is important for the regulation of each of these phenomena. More importantly, perturbations in this pathway are associated with pancreatic cancer. A chief example of these alterations is the mutation
in the TGF-
-regulated transcription factor Smad4/DPC4 that is found
in a large percentage of pancreatic tumors. Surprisingly, studies on
transcription factors have remained an underrepresented area of
pancreatic research. However, the discovery of Smad4/DPC4 as a
transcription factor fueled further studies aimed at characterizing transcription factors involved in normal and neoplastic pancreatic cell
growth. Our laboratory recently described the existence of a novel
family of zinc finger transcription factors, TGF-
-inducible early-response gene (TIEG)1 and TIEG2, from the exocrine pancreas that,
similarly to Smads, participate in the TGF-
response and inhibit
epithelial cell proliferation. This review therefore focuses on
describing the structure and function of these two families of
transcription factor proteins that are becoming key players in the
regulation of pancreatic cell growth.
early-response genes; apoptosis; proliferation; differentiation; zinc finger transcription factor
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INTRODUCTION |
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OVER THE PAST TWO DECADES, extensive
studies have led to the design of a working model to explain how
cells regulate proliferation, differentiation, and apoptosis. For
this purpose, a cell must transduce extracellular signals and translate
them into a program of gene expression. In a number of cell systems,
this occurs by extracellular peptide ligands binding to a cell surface
receptor to initiate a cytoplasmic signaling cascade. This cascade
leads to posttranslational modifications of intracellular proteins that then elicit short-term responses (e.g., cytoskeleton
reorganization or endocytosis) or more long-term responses (e.g., cell
growth). For long-term responses, the signal emanates from the
cytoplasm into the nucleus to regulate transcription factor proteins
that activate or repress the expression of genes necessary for cell growth control (Fig. 1). Therefore, homeostasis of cell
growth relies on an interplay between cell signaling and
transcriptional regulation. This tight control of cellular growth is of
paramount importance for organogenesis and regeneration, and
alterations in these processes lead to embryonic malformations, healing
defects, and neoplastic transformation. One of the best examples
of a signaling pathway that regulates cell growth is that mediated by
transforming growth factor- (TGF-
) peptides in epithelial
cells, the major topic of discussion of this review. Under normal
conditions, TGF-
peptides inhibit epithelial cell proliferation and
induce apoptosis (19, 63). Interestingly, the disruption of this
pathway in many organs, including the pancreas, appears to be an
important step in the development of cancer (19, 62, 80). Thus the identification and characterization of the molecular machinery underlying the ability of TGF-
to control epithelial cell growth will have a remarkable impact on human health.
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TGF-![]() |
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TGF- is a member of an evolutionarily conserved family of secreted
peptides that can modulate cell differentiation, arrest cell
proliferation, and/or induce apoptosis in most epithelial cell populations. Structurally, this family of peptides is grouped into
three major subfamilies: TGF-
s, activins, and bone morphogenetic proteins (BMPs) (for recent reviews, see Refs. 19 and 62). During the
last decade, the identification of both TGF-
receptors and
TGF-
-inducible transcription factors has revealed the existence of a
direct signaling pathway from the cell membrane to the nucleus. This
pathway is responsible for regulating the expression of genes that
control cell growth. The medical relevance of this research is
underscored by the fact that mutations in either TGF-
receptors or
TGF-
-inducible transcription factors result in the failure of cells
to respond to antiproliferative and/or apoptotic signals and in the
development of cancer. This evidence points to the crucial
physiological role of these molecules in the control of normal
epithelial cell growth, differentiation, and apoptosis. Several
excellent reviews have recently been published on the growing field of
TGF-
signaling (1, 19, 62, 63, 80). This review therefore focuses on
recent advances in our understanding of the role of two
TGF-
-regulated transcription factor families, the TGF-
-inducible
early-response gene (TIEG) and Smad proteins, in exocrine pancreatic cells.
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EXOCRINE PANCREATIC EPITHELIAL CELLS ARE A USEFUL MODEL FOR STUDYING
EFFECTS OF TGF-![]() |
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Our laboratory studies cell cycle arrest and apoptosis mediated by
TGF--inducible transcription factors in exocrine pancreatic cell
populations. The pancreas provides an excellent model for studying
TGF-
-based phenomena, and the system is medically relevant because
alterations in this signaling cascade have been associated with the
development of pancreatic cancer (5, 17, 26, 27, 61, 82). The adult
pancreas contains an endocrine portion comprised of four different cell
populations (
,
,
, and
) and an exocrine portion comprised
of acinar and ductular cells. Interestingly, all six of these
pancreatic cell populations are believed to originate from an
epithelial "ductular-like" precursor, a phenotype that is
characteristic of cancerous pancreatic cells (10).
The effects of TGF- on pancreatic cell differentiation were
originally examined using a whole organ culture system. In this system,
TGF-
has an inhibitory effect on acinar cell growth but also
increases the number of islet cells differentiated from ductular-like structures, indicating that TGF-
may exert differential effects on
cell differentiation in a cell-specific manner (30, 73). The central
role of TGF-
in both pancreatic cell differentiation and growth has
recently been confirmed and extended in vivo using transgenic
animals. For example, overexpression of TGF-
1 specifically in the
pancreatic
-cells of transgenic mice not only alters islet cell
development but also inhibits acinar cell proliferation (52, 74).
Furthermore, transgenic mice that express a dominant-negative TGF-
receptor type II in the acinar cells of the pancreas (rendering these
cells insensitive to TGF-
signaling) exhibit increased proliferation
and perturbed differentiation of acinar cells (9). Together, these
results confirm that TGF-
signaling exerts a negative effect on
acinar cell growth and that it is also necessary for maintaining the
differentiation status of both acinar and islet cells.
Other useful models for studying the growth-regulatory effects of
TGF- in pancreas are provided by several transformed cell lines
derived from human pancreatic cancers or chemically induced tumors from
experimental animals. For example, several of these exocrine pancreatic
cell lines are responsive to TGF-
peptides and can be used for in
vitro anchorage-dependent and -independent cell growth assays (5, 20,
33, 41, 43, 45, 46, 51, 55, 72, 83). In addition, because these cells
often carry complex genetic alterations, including mutations in several mediators of TGF-
signaling, the results obtained from using these
lines can be informative when dissecting specific defects in this
pathway (5, 23, 33, 83, 85). Furthermore, the data described above are
in agreement with a previous report by Logsdon et al. (60) that
described for the first time the growth-inhibitory effects of TGF-
on normal isolated pancreatic acinar cells, validating the
extrapolation of results obtained in cell lines to physiological conditions. In summary, a large variety of experimental models exist
for testing the role of TGF-
on pancreatic cell growth in vitro
and in vivo, namely pancreas explants, isolated cell populations, and transgenic animal models. The theoretical framework emerging from the combined use of these systems points toward an
essential role for the TGF-
pathway in pancreatic organogenesis and
tumor suppression. Finally, we are optimistic that many of the concepts
derived by using pancreatic cells can be applied to other epithelial
cell systems.
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MEMBRANE-TO-NUCLEUS TGF-![]() |
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The discovery of DPC4 (deleted in pancreatic cancer 4) as a
putative tumor suppressor gene for pancreatic cancer in 1996 was a
breakthrough in the field of pancreatic cell research
(35). The finding that the product of
DPC4 was structurally related to Mad, a protein involved in
TGF--related signaling in Drosophila, paved the way toward
the identification of an entire family of Smad proteins that function
as important mediators of TGF-
signaling pathways (50, 58).
Currently, eight different Smad-encoding genes have been isolated from
mammalian cell populations (Smad 1-8), and they are
classified into three different subfamilies: receptor-regulated Smads
(R-Smads), co-Smads, and anti-Smads (see Refs. 4, 49, 62, and 86 for
reviews). The R-Smads bind to a specific TGF-
-related receptor at
the cell surface, are phosphorylated at their COOH termini on ligand
stimulation, associate with a co-Smad, and translocate into the nucleus
to regulate gene expression (Fig.
2A). R-Smads 2 and 3 both
participate in TGF-
and activin signaling, whereas R-Smads 1, 5, and
8 participate in BMP-mediated signaling. In contrast, the only co-Smad
identified thus far, Smad4/DPC4, associates with Smads 1-3 and 5 and thus participates in TGF-
, activin, and BMP signaling. Finally,
Smad6 and Smad7 function as anti-Smads by interfering with R-Smad
function. This interference occurs either by binding to the TGF-
receptor, blocking phosphorylation of R-Smads (Smad6), or by binding
directly to an R-Smad to prevent interaction with Smad4 (Smad7).
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MODULAR STRUCTURE OF SMAD PROTEINS |
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The Smad proteins share a general structure containing two highly
conserved domains, most commonly referred to as Mad homology domains 1 and 2 (MH1 and MH2), separated by a variable proline-rich linker region
(Fig. 2B). Within the R-Smads and co-Smads, the MH1 domain,
located at the NH2 terminus, is a 130-amino acid sequence that serves as a unique DNA binding motif. The anti-Smads, however, have limited homology within this domain, and consequently have not
been shown to behave as DNA binding proteins. DNA binding activity of
Smad proteins was first observed in Drosophila melanogaster, in
which Kim et al. (44) demonstrated that the MH1 domain of Mad, when
fused to the heterologous Gal4 transactivation domain, could regulate a
number of target genes of the TGF--like peptide Dpp. Since this
finding, several studies have begun to define a consensus binding site
for Smad proteins in mammalian cells. Experiments using endogenous
target gene promoters as well as random oligonucleotide binding assays
have demonstrated that the consensus binding site for Smads contains a
core AGAC sequence (18, 21, 59, 84, 90). Interestingly, however,
TGF-
-like response genes often require the presence of not only Smad
binding sites but also binding sites for other transcription factors to achieve appropriate expression. The activin-inducible gene,
Mix.2, for example, requires the interaction between Smad2 and
the DNA binding protein forkhead activin signal
transducer-1 (FAST-1) to regulate its expression (11). FAST-1 is
a hepatocyte nuclear factor-
(HNF-
)/forkhead-related
transcription factor that was shown to bind to Smad2 in a yeast
two-hybrid screen (12). Subsequent studies demonstrated
that Smad2/Smad4 or FAST-1 alone is unable to regulate Mix.2
expression but together drive activin-dependent activation.
Furthermore, binding of FAST-1 to a site located directly upstream of
the Smad2 binding site is necessary for this regulation (12, 59).
Together, these data suggest that DNA binding specificity of the Smad
proteins is facilitated by cooperative binding with other transcription
factors. This hypothesis has been further supported by
recent reports demonstrating cooperative transcriptional regulation of gene expression through interaction with the
transcription factors AP-1, Sp1, transcription factor µE3, and the
vitamin D receptor (VDR) (37, 66, 89, 92). These studies
lend insight into the mechanisms underlying promoter recognition by the
Smad proteins, a crucial step toward defining in vivo targets of
TGF-
signaling.
The MH2 domain, located at the COOH terminus of the Smad proteins, is
highly conserved among all family members and is important for several
functional processes, including homo- and heterooligomerization, receptor binding, nuclear localization, phosphorylation, and
transcriptional regulation (36, 62, 86). Under resting conditions, the
MH2 domain is important for association of the R-Smads to their cognate receptors as well as homotrimerization of the Smad molecules, an
association that appears to maintain them in an inactive state. On
ligand stimulation, a SSXS motif at the very COOH terminus of the
R-Smads is phosphorylated by its receptor, allowing heterodimerization between the R-Smads and the co-Smads and translocation into the nucleus. Once in the nucleus, the R-Smad/co-Smad complex binds to DNA,
where it can either activate or repress transcription. The ability of
Smads to behave as activators or repressors appears to depend on the
interaction of the MH2 domain of these proteins with cofactors that
either affect chromatin structure or interact with the basal
transcriptional apparatus. For example, CBP/p300, a histone
acetyltransferase oncoprotein that loosens nucleosome structure,
interacts with various Smads to facilitate transcriptional initiation
(22, 39, 67, 70, 76, 81). Conversely, another Smad2-interacting
cofactor, TG sequence-interacting factor (TGIF), is a homeodomain
protein that recruits a histone deacetylase complex to repress
transcription (87). This finding is important because TGF- signaling
involves not only the activation of gene expression but also
transcriptional repression (62). Therefore, through the selective
interaction with histone acetylases and deacetylases, Smads are capable
of increasing or decreasing gene expression, respectively, underscoring
the importance of Smad-mediated transcriptional regulation in TGF-
signaling.
Finally, the linker domain of Smad proteins contains consensus tyrosine
phosphorylation sites that are targets of various signaling cascades
that regulate their functions. For instance, sites within the linker
regions of Smad1, 2, and 3 are phosphorylated by mitogen-activated
protein (MAP) kinase in response to epidermal growth factor (EGF),
resulting in their inactivation (47, 48). Similarly, an oncogenic form
of Ras interferes with the function of Smad2 and Smad3 through MAP
kinase-mediated phosphorylation (48). Thus inactivation of Smads by
linker phosphorylation can be used by EGF to antagonize the
antiproliferative signals from TGF-. Because the linker region
varies significantly in structure among the Smads, different
phosphorylation sites may provide a mechanism for distinct signaling
cascades to differentially regulate the Smad proteins.
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SMAD PROTEINS IN PANCREATIC CELL GROWTH |
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Although several of the experiments described above have been performed
in other ductular epithelial cells such as breast cancer cells,
emerging evidence indicates that Smad-mediated processes are
fundamental for maintaining the homeostasis of pancreatic cells. The
finding that DPC4/Smad4 is mutated in ~50% of pancreatic cancers suggested its participation in a signaling pathway that suppresses neoplastic cell growth in this gland (35). This hypothesis has been further supported by the finding that TGF- requires DPC4 to
inhibit pancreatic cell growth through the upregulation of the cell
cycle inhibitor protein p21waf1 (33). Furthermore, recent
studies have revealed the role of other members of the Smad family in
the regulation of TGF-
signaling and pancreatic cell growth. For
instance, the anti-Smad protein, Smad6, has been found to antagonize
the growth-inhibitory effects of TGF-
in pancreatic carcinoma cell
lines and is overexpressed in pancreatic tumors (45). This mechanism
may contribute to the resistance to TGF-
signaling that is
frequently observed in neoplastic pancreatic cell populations.
Together, these studies indicate that both mutations in Smads involved
in mediating the TGF-
response and overexpression of anti-Smads are
associated with uncontrolled pancreatic cell growth. Thus studies aimed
at experimentally modifying these proteins may be useful for devising therapeutic agents for neoplastic diseases of the pancreas.
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EARLY-RESPONSE GENES FOR TGF-![]() |
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The activation of transcription factors is an absolute requirement for
eliciting long-term cellular responses to an extracellular signaling
cascade. This mechanism in turn switches on and off the expression of
genes that are necessary for a particular cellular event such as
proliferation, differentiation, or apoptosis. The first genes to be
turned on by a signaling cascade are called "early-response
genes." Because of the immediate need for these gene products to
respond to an extracellular stimulus, the cellular machinery necessary
for their expression is constitutively present in the cell. Thus
activation of early-response genes occurs in the absence of de
novo protein synthesis. Many of the early-response genes that have
been identified for TGF- signaling are oncogenic transcription
factors (e.g., c-fos, c-jun, and c-myc),
pointing to the importance of early-response genes in maintaining
normal cell growth (54, 69, 78, 91). As a result of our interest in the
regulation of pancreatic epithelial cell growth and neoplastic transformation, we recently revealed the existence of a novel family of
pancreas-enriched transcription factors, TIEG1 and
TIEG2, that are early-response genes for TGF-
and inhibit
epithelial cell proliferation (14, 79) (Fig.
3).
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The human homolog of TIEG1 was originally identified as the
product of a TGF--inducible early-response gene from osteoblastic cell populations using differential display PCR (77). Our laboratory subsequently reported the cloning of TIEG1 from a rat pancreas cDNA library (79). Interestingly, TIEG1 has also been
identified as a growth factor-inducible gene from prostate and brain,
where it has received the names early growth response gene-
(EGR-
) and glial cell-derived neurotrophic factor inducible
transcription factor (GIF), respectively (8, 88). These
data support a role for TIEG1 in the regulation of growth in many cell
systems. In addition, we have recently reported the identification of
TIEG2, a protein structurally related to TIEG1 (14). These two proteins are 91% similar within the COOH-terminal DNA binding domain and 44%
similar throughout a proline-rich NH2-terminal domain (Fig. 3). Like TIEG1, TIEG2 is also an early-response gene
for TGF-
in pancreatic cell populations (14). Thus on the basis of
their sequence similarity and TGF-
inducibility, TIEG1 and TIEG2
represent a distinct group of transcription factors.
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MODULAR STRUCTURE OF TIEG PROTEINS |
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With the goal of understanding better the function of TIEG1 and TIEG2,
we characterized the biochemical properties of these proteins. One of
the most striking features of these proteins is that they each possess
three structurally related zinc finger DNA binding motifs at the COOH
terminus that share strong homology with members of the Sp1-like family
of zinc finger transcription factors. The founding member of this
family, Sp1, uses this motif to bind to GC-rich sequences (40).
Interestingly, these GC-rich sequences contribute to the regulation of
a large number of growth-regulatory genes, including cell cycle
regulators (p15, p21, p27), MAP kinases (MAPK),
mitogenic GTPases (H-ras), DNA synthesis proteins
[histones, thymidine kinase, dihydrofolate reductase (DHFR), DNA
polymerase (POLD1)], growth factors [platelet-derived
growth factor (PDGF), TGF-
, fibroblast growth factor (FGF),
granulocyte macrophage colony-stimulating factor (GMCSF), tumor
necrosis factor-
(TNF-
)], and growth factor receptors
(insulin receptor and insulin-like growth factor receptor) (2, 3, 6, 7,
29, 38, 42, 53, 56, 57, 64, 65, 68, 71, 93, 94).
Therefore, it is not surprising to find that many of the Sp1-like
family members function as key regulators of morphogenesis (reviewed in
Ref. 15). As predicted from structural analysis, biochemical studies of
TIEG1 and TIEG2 demonstrate that both of these proteins recognize
Sp1-related GC-rich sequences (14, 16, 88). Of particular interest,
however, is that although the majority of Sp1-related proteins function
to activate gene expression, both TIEG proteins function as potent
transcriptional repressors (13, 15, 88). This repression activity
resides within the region of these proteins located
NH2-terminal to the zinc finger DNA binding motif.
Furthermore, mutational analysis of the NH2 terminus has
revealed the presence of three conserved motifs that function as strong
repressors (13). In addition, a basic tetrapeptide within the second
zinc finger of TIEG2 functions as a nuclear localization signal (NLS)
(Ref. 28 and unpublished data). Finally, four linker regions separate
the transcriptional repressor and DNA binding motifs. Although the role
of these linker regions currently remains undefined, they contain
numerous sites for posttranslational modifications that may be targets
for different signaling pathways (V. Ellenreider and R. Urrutia,
unpublished data). Thus, like the Smads, TIEG transcription factors are
modular proteins containing a DNA binding motif, an NLS, a
transcriptional regulatory domain, and linker regions that contain
sites for posttranslational modifications. Together, these data support
a model in which TGF-
binds to its cell surface receptor to induce
the expression of TIEG1 and TIEG2, which in turn bind to GC-rich
sequences to repress genes necessary for inhibiting epithelial cell growth.
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TIEG PROTEINS INHIBIT EPITHELIAL CELL GROWTH |
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The molecular and biochemical characterization of TIEG proteins
described above supports a role for these transcription factors as
links between TGF- signaling cascades and the regulation of nuclear
events. To test this role, we characterized the growth-regulatory properties of these proteins both in vitro and in vivo. In vitro studies of TIEG1 revealed that overexpression of this gene in the
TGF-
-sensitive exocrine pancreatic cell line PANC-1 inhibits cell
proliferation and also induces apoptosis (Fig.
4, A-C; Ref. 79). These results demonstrate that the increased
intracellular levels of TIEG1 achieved using transient transfection
mimic the antiproliferative and apoptotic effects of TGF-
on
epithelial cell growth, suggesting that TIEG1 is an important factor
for mediating TGF-
signaling. Similar studies performed with TIEG2 indicate that this TGF-
-inducible transcription factor is also sufficient to inhibit epithelial cell proliferation (14). Together, the
TGF-
inducibility and the growth-inhibitory properties of the TIEG
proteins suggest that these transcription factors may function as
signal transducer molecules for TGF-
-regulated cell growth.
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To better understand the role of TIEG proteins in vivo, we have
recently used the elastase I promoter to generate transgenic mice that
express TIEG2 in the acinar cells of the exocrine pancreas (65).
Morphological evaluation of the pancreas at 12 wk revealed a remarkable
degree of acinar cell pleomorphism, an increase in the
nucleus-to-cytoplasm ratio, and incipient loss of the acini-like organization (Fig. 4, D-F). Interestingly, these changes
are reminiscent of the early stages of pancreatic atrophy previously
described in mice overexpressing TGF-1. Furthermore, TIEG2
transgenic pancreata show an increase in the rate of apoptosis, one of
the expected outcomes of expression of a protein that works in the
TGF-
pathway to control pancreatic cell growth (A. Mladek and R. Urrutia, unpublished data). These results demonstrate that normal
levels of the TGF-
-inducible transcription factor TIEG2 are
necessary for maintenance of the homeostasis of pancreatic acinar cells
and that perturbations in this pathway can result in significant
alterations in pancreatic morphogenesis.
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DIFFERENCES BETWEEN SMAD AND TIEG PROTEINS |
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The preceding paragraphs mainly stress the similarities between Smads
and TIEG proteins that have been described thus far. However, some
important differences between these two families of proteins must be
considered. For instance, Smads interact directly with the TGF-
receptor at the cytosolic surface of the cell membrane and move into
the nucleus on activation of this signaling cascade. Whether TIEG
proteins behave in a similar fashion remains to be established. On the
basis of the pattern of expression of TIEG1 and TIEG2, however, these
transcription factors appear to be downstream of the Smad proteins. It
should also be mentioned, however, that by immunohistochemistry, TIEG1
has been found in both the cytoplasm and the nucleus of exocrine
pancreatic cells. (79). Thus it remains a possibility that, similar to
the Smads, TIEG proteins undergo nuclear translocation in response to
distinct signaling cascades.
In addition to differences between Smad and TIEG proteins, it is also likely that future studies will uncover distinct roles for each of the TIEG proteins. Currently, no differences in the transcriptional regulatory or DNA binding properties have been observed (Ref. 13; T. Cook, A. Mladek, and R. Urrutia, unpublished data). However, it is unlikely that these two proteins exist within a single cell population to perform the same function. Therefore, ongoing studies aimed at determining the exact function of TIEG1 and TIEG2 in vivo will be critical for understanding the participation of each of these proteins in the regulation of pancreatic cell growth.
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ALTERATIONS IN TGF-![]() |
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As described in this review, diverse experimental approaches reveal
that the normal functioning of TGF- signaling is essential for the
homeostasis of pancreatic cell physiology. Because of the importance of
TGF-
signaling in the regulation of normal pancreatic cell growth
and differentiation, it can be predicted that alterations in these
pathways will result in pancreatic diseases. Indeed, several studies
have suggested that many, if not all, pancreatic tumor cells exhibit
nonfunctional TGF-
signaling (5, 46, 61, 83). Furthermore,
alterations in many components within the TGF-
signaling pathway,
including TGF-
ligands, receptors, Smads, and early-response
transcription factors, have been associated with pancreatitis and
pancreatic cancer (5, 23-27, 31, 32, 34, 45, 61, 75, 82, 83, 85).
Here, we have reviewed the important roles of two families of
transcription factor proteins, the Smads and TIEGs, as critical
mediators of the TGF-
response of pancreatic cells. In addition, we
have described the most recent and fundamental studies devoted to the
molecular, biochemical, and functional characterization of these
proteins. Although these studies constitute an exciting beginning, much
more remains to be learned about the role of these proteins in
pancreatic cell physiology and disease. This endeavor will certainly
involve the combined efforts of several laboratories around the world
and will provide the theoretical framework for a new generation of investigators dedicated to understanding the integration of signaling cascades and gene expression. The translation of this basic knowledge into understanding of the mechanisms of pancreatic disease, however, currently constitutes one of the most challenging efforts facing molecular medicine today.
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ACKNOWLEDGEMENTS |
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The authors thank Brian Gebelein, Karen Hedin, and Vijay Shaw for critically reviewing the manuscript.
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FOOTNOTES |
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This work was supported by the Mayo Cancer Center and by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant DK-52913 to R. Urrutia. T. Cook was supported by NIDDK Training Grant DK-07198.
Current address for T. Cook: 100 Washington Square E., 1009 Main Building, New York Univ., New York, NY 10003.
Address for reprint requests and other correspondence: R. Urrutia, Gastroenterology Research Unit, 2-445A Alfred Bldg., Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (E-mail: urrutia.raul{at}mayo.edu).
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