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Institute of Molecular Animal Breeding, Gene Center, D-81377 Munich, Germany
1Correspondence: Institute of Molecular Animal Breeding, Gene Center, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany. E-mail: ewolf{at}lmb.uni-muenchen.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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Key Words: IGFBP • insulin-like growth factors • transgenic mice • overexpression • knockout
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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. These
features, which hamper their analysis using classical experimental
approaches of endocrinology, make the use of transgenic models
specifically attractive for unraveling the determinants of growth
factor expression and their target cell response during embryonic and
fetal development as well as in the adult animal (2)
.
The insulin-like growth factors (IGFs), IGF-I and IGF-II, are a pair of
small single-chain peptides that share significant structural homology
with insulin (3)
. They are involved in regulation of cell
growth, differentiation, and metabolism, eliciting diverse effects in a
plethora of biological processes (4)
. The biological
effects of IGFs are achieved through binding to high-affinity receptors
on the cell surface. The type I IGF receptor (IGF-I-R) is, like the
insulin receptor, a heterotetrameric protein complex containing a
tyrosine kinase domain that mediates signal transduction
(5)
. Its inactivation leads invariably to severe neonatal
growth deficiencies as a consequence of hypoplasia in several tissues.
Nevertheless, these animals are born alive but die within minutes due
to respiratory failure (6)
. The structurally distinct
IGF-II-R is a monomeric protein lacking tyrosine kinase activity and is
also known as the cation-independent mannose-6-phosphate receptor.
There is no known signal transduction mechanism that is initiated by
this receptor, and all proliferative effects of the IGFs are thought to
be mediated through the IGF-I-R (7)
. However, the IGF-II-R
plays an important role for the degradation of IGF-II. Inactivation of
IGF-II-R expression in mice by gene targeting results in fetal
overgrowth, skeletal abnormalities, and perinatal death due to
overexposition of fetuses to IGF-II (8
9
10)
.
Unlike insulin, the IGFs are bound in serum and other biological fluids
to a family of six structurally and evolutionary related binding
proteins, termed IGF-binding proteins (IGFBP-1 to IGFBP-6) (Table 1
). In the circulation, ~75–80% of the IGFs are present in a complex
of 150 kDa, composed of one molecule of IGF-I or IGF-II, a 85 kDa
acid-labile subunit (ALS), and IGFBP-3. A smaller proportion (20–25%)
of the IGFs is associated with other IGFBPs forming a 50 kDa complex,
and less than 1% is found in free form of ~7.5 kDa
(26)
.
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The IGFBPs are expressed in a tissue-specific manner and have different
affinities for the IGFs. Besides their role in preventing insulin-like
side effects of the relatively large concentrations of IGFs in the
circulation, IGFBPs are able to modulate different IGF actions
positively or negatively; recent evidence suggests they can also exert
IGF-independent effects (26
27
28)
. Actually, these proteins
are part of a superfamily that comprises the six high-affinity IGFBPs
and at least four other low-affinity IGF binders, termed insulin-like
growth factor binding protein-related proteins (IGFBP-rP)
(29)
. Finally, at least three mechanisms have been shown
to alter the affinity of the IGFBPs to IGFs, making the network of
regulatory components in the IGF system even more complex: IGFBP
proteolysis, phosphorylation, and adherence to the cell surface or to
the extracellular matrix (30)
.
The accumulation of experimental evidence of the intrinsic importance
of IGFBPs in modulating IGF actions caused them to be an object of
great interest, now occupying a front position in IGF and growth factor
research. However, the precise roles of individual IGFBPs are still
unknown, due mainly to the great complexity of their actions and their
regulation, but also to the fact that the overwhelming majority of
information about the IGFBPs is derived from in vitro
studies. Nonphysiological concentrations of the IGFs and their binding
proteins as well as the lack of other components such as the IGFBP-rPs
may lead to artificial culture conditions, which can explain confusing
and sometimes contradictory results obtained from these studies
(31)
.
In many situations of physiological or pathological growth, multiple
components of the IGF system may be dysregulated (4
, 32
33
34
35)
. It is therefore difficult to predict which components
are responsible for altered growth and which ones are only coregulated
without an intrinsic effect on growth and differentiation. Transgenic
and knockout strategies in model organisms provide a unique opportunity
of performing gain of function, partial loss of function, and loss of
function studies for a particular gene. Consequently, effects of
altered expression of a member of the IGF system on the other
components of the system and the phenotypic consequences can be
precisely studied. More recently, this can be performed in an inducible
and/or tissue-specific or stage-specific manner. For technical details,
the reader is referred to recent reviews and textbooks
(36
37
38
39
40)
.
Many transgenic and knockout mouse models for the ligands (41
, 42)
, receptors (43)
, and binding proteins of the
IGF system were developed in the last decade. The knockout approach,
when applied to ligands and receptors, resulted in exuberant
phenotypes. In contrast, when applied to the binding proteins, the
results were rather disappointing: in IGFBP-2 knockout mice, a
reduction in spleen weight of adult males was the only morphological
alteration (44)
; IGFBP-4 mutants appear to be slightly
smaller than normal counterparts, and the genetic ablation of IGFBP-6
has not resulted in any apparent phenotypical manifestation
(45)
. It is reasonable to speculate that functional
compensation by other members of the IGFBP family (including the
recently described IGFBP-rPs) may prevent the appearance of dramatic
phenotypes. The alternative approach, namely, the overexpression of
IGFBPs in transgenic mice, has been far more successful in producing
both expected and unexpected phenotypes. This review presents an
overview of transgenic models that have been developed to date for the
study of IGFBP functions in vivo and discusses the data
obtained from these experiments.
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IGFBP-1 |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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.
With the publication of its complete cDNA in 1988 (47)
, it
became the first characterized member of the IGFBP family. In the
developing mouse, IGFBP-1 expression can be detected in day 13.5 whole
embryo preparations. In the adult mouse, its expression appears to be
restricted to the liver, being high during the first days of postnatal
life and decaying thereafter (Table 1)
. Although it may stimulate IGF
actions under some conditions, the vast majority of in vitro
studies indicates that IGFBP-1 mainly inhibits IGF-dependent cellular
growth and differentiation (27)
. The biological actions of
IGFBP-1 are associated with basically three aspects of physiology:
carbohydrate metabolism, female reproductive functions, and fetal
growth. Further information about IGFBP-1 actions, gene structure and
expression can be found in a comprehensive review (48)
and
its recent update (49)
.
Three different transgenic models overexpressing this protein have been
developed (Table 2
). D’Ercole et al. (50)
reported the generation of three
strains of transgenic mice harboring a fusion gene in which the human
IGFBP-1 cDNA was placed under the control of the mouse
metallothionein-I promoter (MT). In addition to a wide tissue
expression (51)
all three lines ectopically express
IGFBP-1 in the brain. The generation of four strains of transgenic mice
expressing the rat IGFBP-1 gene under the control of the mouse
phosphoglycerate kinase promoter (PGK) was reported by Rajkumar et al.
(52)
. High levels of transgene expression were detected in
the offspring, especially in brain, uterus, lung, and kidney. Gay et
al. (11)
reported the development of two strains of
transgenic mice carrying the human IGFBP-1 cDNA under the control of
the human 
1-antitrypsin (1 AT) promoter, which directs the
expression of the transgene to the liver.
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Phenotypical consequences of IGFBP-1 transgene expression
Brain development and growth
Reduced brain weight associated with specific morphological
alterations was a common feature of all three IGFBP-1 transgenic models
(Table 3
). The MT-hIGFBP-1 mice exhibit brain growth retardation beginning in
the second week of postnatal life, which persists when brain weight is
calculated as a function of body weight. Further analyses confirmed
multiple alterations in brain development and morphology
(58
59
60)
.
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In the PGK-rIGFBP-1 model, the brain was the only organ showing
significant weight reduction (52)
. The neuroanatomical
deficits and other parameters such as cell proliferation and apoptosis
in the brain of PGK-rIGFBP-1 mice were further evaluated by Ni et al.
(62)
.
Hydrocephalus was observed in 50% of 1 AT-hIGFBP-1 homozygotes,
which also had lower brain weights than controls. Examination of brain
sections showed dilation of the ventricles, reduced width of the
cerebral cortex, and disorganization of its architecture, together with
atrophy of the corpus callosum and hippocampus (11)
.
The IGFs are potent agents that stimulate proliferation and/or survival
of neural cells in vitro and are essential factors for
normal development of the nervous system in vivo
(4)
. Indeed, the mammalian nervous system is a site of
intense and well-documented IGF activity (69)
. In the
mouse, the brain is normally not a site of IGFBP-1 expression
(25)
, and despite its identification in the neuromuscular
synapse (70)
, no significant functions are attributed to
IGFBP-1 in the central nervous system. Several lines of evidence
indicate conclusively that brain growth retardation observed in these
transgenic models is a direct and specific consequence of high levels
of IGFBP-1 in the brain and related to its capacity to bind and to
inhibit the stimulatory actions of IGF. 1) The same effect
was observed in all three transgenic models, each carrying a different
fusion gene. 2) The effect was associated with a high level
of hIGFBP-1 expression in the brain of MT-hIGFBP-1 and PGK-rIGFBP-1
models, and with high and constant serum IGFBP-1 levels in the 1
AT-hIGFBP-1 model. 3) Transgene expression in the
MT-hIGFBP-1 model occurred in regions (cerebral and piriform cortex,
hippocampus, thalamus, and hypothalamus) known to be sites of IGF-I
expression during the first month of postnatal life (71)
,
exactly at the same time the alteration was observed. 4)
Mice overexpressing IGF-I in the brain under the control of the MT
promoter display a phenotype inverse to that of MT-hIGFBP-1 transgenic
mice in many aspects (72)
.
Somatic growth
In PGK-rIGFBP-1 transgenic mice, the birth weight was
significantly reduced to ~83–92% of the weight of wild-type animals
(52)
. The growth retardation was also present postnatally,
particularly after weaning. Except for brain (which was
disproportionately reduced; see above) and spleen (which was heavier),
the absolute weights of individual organs were reduced in transgenic
mice, but similar to those of control mice when considered as a
function of body weight.
1 AT-hIGFBP-1 transgenic animals show growth retardation within the
first weeks of postnatal life. Body weight of adult mice was negatively
correlated with IGFBP-1 plasma concentrations, further supporting a
relationship between phenotype and transgene expression
(11)
. It remains to be elucidated whether overexpression
of IGFBP-1 has different effects in specific organs as observed in the
PGK-rIGFBP-1 model.
The IGFs are undoubtedly involved in the regulation of fetal growth.
Knockout mice lacking IGF-I, IGF-II or IGF-I-R are born with marked
growth retardation (73)
. In humans, there is a direct
correlation between cord blood IGF-I concentration and fetal size and
birth weight (74)
. Likewise, IGFBP-1 is involved in
intrauterine growth regulation in humans (49)
and rodents
(75
, 76)
. Insulin, whose inactivation results in growth
retardation and neonatal lethality in mice (77)
,
positively regulates the expression of IGFBP-1 (49)
as
does hypoxia (78)
. Taken together, these data indicate
that IGFBP-1 may be an important regulator of fetal growth, probably by
limiting the availability of IGFs to their target tissues under
conditions of hypoxia or restricted substrate availability.
In the 1 AT-hIGFBP-1 transgenic mice, abnormally high and constant
levels of IGFBP-1 in the bloodstream are likely to be responsible for
impaired somatic growth. Although serum levels of IGFBP-1 in
PGK-rIGFBP-1 transgenic mice were not markedly higher than in control
animals, the elevated tissue levels can be responsible for inhibiting
IGF actions, thereby causing overall weight reduction. The fact that
growth retardation was present at birth in PGK-rIGFBP-1 animals may be
a consequence of the ubiquitous expression provided by the PGK promoter
and the consequent stronger IGFBP-1 inhibitory effect.
Glucose homeostasis
Rajkumar et al. (63)
reported that in addition to the
fasting hyperglycemia observed in homozygous male PGK-rIGFBP-1
transgenic mice (52)
, these animals also demonstrated
fasting hyperinsulinemia and glucose intolerance. The sensitivity to
insulin, however, was not altered. The relative weight of the pancreas
was increased. They also observed that pancreatic islets were
significantly larger and more numerous than in wild-type mice, although
pancreatic insulin content was reduced. Alterations of pancreas
structure and function, as well as of glucose metabolism, in the
PGK-rIGFBP-1 model were investigated in more detail in further studies
(64
65
66
67)
. In 1 AT-hIGFBP-1 homozygous transgenic mice,
glucose tolerance was also affected (11)
.
In addition to the general role of IGFBPs in limiting the potential
hypoglycemic effects of IGFs, a specific role in the regulation of
carbohydrate metabolism has been proposed for IGFBP-1
(48)
. When administered intravenously together with IGF-I
in rats, IGFBP-1 blocked its hypoglycemic effects and increased blood
glucose levels when administered alone (79)
. In addition,
the promoter region of the IGFBP-1 gene is similar to that of the gene
coding for phosphoenolpyruvate carboxykinase, a key enzyme in the
regulation of gluconeogenesis. In contrast to glucagon and
glucocorticoids, which stimulate transcription, insulin is a potent
inhibitor of both basal and stimulated IGFBP-1 expression
(80)
.
Although the hyperglycemia observed in transgenic mice is easily
explained by IGFBP-1 inhibiting the hypoglycemic effect of free IGFs,
the reason for the abnormalities observed in the pancreas of
PGK-rIGFBP-1 animals is not that obvious. However, as suggested by the
authors, the impaired pancreatic function may be a consequence of
persistent hyperglycemia, which would also explain the insulin
depletion (63)
.
Reproductive performance
The observation that litter size was reduced during the generation
of PGK-rIGFBP-1 homozygous strains led Huang et al. (68)
to examine this aspect in detail in one strain that strongly expressed
IGFBP-1. The expression of the transgenic IGFBP-1 in the ovary was
detected by Northern analysis. The authors observed that compared to
wild-type mice, naturally mated transgenic mice had a significantly
reduced number of corpora lutea and significantly fewer blastocysts
could be harvested by flushing the uterine horns. Basal DNA synthesis
and total DNA content of wild-type and transgenic blastocysts were
similar, but the latter did not respond to exogenous IGF-I with DNA
synthesis.
The reproductive performance of 1 AT-hIGFBP-1 transgenic mice was
impaired in several aspects, especially in homozygous females. The
changes included a reduced percentage of matings resulting in
pregnancy, interrupted or prolonged pregnancies with fetal or neonatal
death (accordingly, homozygotes represented two-thirds of the dead
pups), and a reduced litter size.
Although present in the human ovary and apparently involved in its
physiology and pathology (49)
, IGFBP-1 normally is not
expressed at detectable levels in the mouse ovary. This circumstance
associated with the characteristics of impaired fertility indicates
that the main element affecting the reproductive performance of
PGK-rIGFBP-1 transgenic mice is reduced ovulation as a consequence of
the ectopical expression of IGFBP-1 in the ovaries.
The origin of the impaired fertility of 1 AT-hIGFBP-1 transgenic
mice remains unclear. Several studies indicate that IGFBP-1 is not only
involved in cyclic alterations of ovary and uterus, but also in
blastocyst implantation, acting as a maternal ‘restraint’ on
trophoblast invasion (49)
. This could be an alternative or
an additional mechanism leading to impaired fertility in these animals.
However, it appears to be a consequence of high IGFBP-1 serum levels,
since no transgene expression was detected in ovary or uterus, and
several other systems were affected without showing any expression of
the transgene.
Other effects
Besides the main effects discussed above, several other
alterations were observed in IGFBP-1 transgenic mice (Table 3)
. For
instance, 1 AT-hIGFBP-1 animals show proteinuria and glomerulus
lesions (11)
. This is a very interesting finding since
some components of the IGF system are known to be aberrantly expressed
in pathophysiological processes associated with diabetic renal disease
(83)
. The relative increase of spleen weight observed in
PGK-rIGFBP-1 animals (52)
may be a consequence of
IGF-independent actions of IGFBP-1. However, this does not apply to the
altered tolerance and sensitivity to ethanol in MT-hIGFBP-1 mice
(61)
.
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IGFBP-2 |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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). Serum IGFBP-2 levels are increased in transgenic
mouse models overexpressing IGF-II, suggesting a regulation of IGFBP-2
expression by its primary ligand (82
, 83)
. Increased
levels of serum IGFBP-2 are found after fasting and in a number of
pathological conditions, including non-islet cell tumor hypoglycemia,
diabetes mellitus, chronic renal failure, liver cirrhosis, and certain
types of leukemia (reviewed in ref 84
).
Knockout mice lacking IGFBP-2 expression did not show overt
phenotypic alterations. The only morphological difference appeared to
be the size of the adult male spleen, which was reduced by ~30%.
However, the concomitant up-regulation of other IGFBPs and the
functional redundancy within this family of related proteins might have
hidden intrinsic effects of IGFBP-2 (44
, 85
, 86)
. There is
indirect evidence for a role of IGFBP-2 as an inhibitor of IGF actions.
First, reduced growth of mice selected for low body weight was
associated with increased hepatic IGFBP-2 mRNA expression and IGFBP-2
serum levels (87)
. Second, transgenic rabbits expressing
high levels of recombinant human IGF-I in their mammary glands did not
show any phenotypic alterations. Ligand blot analysis of milk from
these transgenic rabbits revealed a marked increase in the activity of
IGFBP-2 that might have buffered effects of excess IGF-I
(88)
. Direct evidence for an IGF-inhibitory role of
IGFBP-2 comes from cell culture studies. IGFBP-2 inhibited
IGF-II-dependent autocrine growth stimulation of human colon carcinoma
cells but did not affect proliferation of IGF-resistant cells
(89)
.
To characterize effects of excess IGFBP-2 in vivo, we
generated transgenic mice expressing a mouse IGFBP-2 cDNA under the
control of the CMV promoter (54)
. Transgene expression was
detectable in nearly every organ tested with exception of the liver.
Transgenic mice were characterized by threefold increased IGFBP-2 serum
levels if compared to nontransgenic littermates (Table 2)
. Despite
abundant transgene expression in most of the organs, organ weights were
only moderately reduced (
3%) in IGFBP-2 transgenic mice. The weight
reductions were most prominent in pancreas, spleen, and liver. It is
important to point out that it is precisely these organs that showed
the greatest increase in weight in IGF transgenic mice
(90)
. A similar inverse phenotype was seen for the carcass
weight: IGFBP-2 overexpression decreased carcass weight by 12–13%
(54)
whereas IGF-I overexpression resulted in a 20%
increase (90)
. IGFBP-2 transgene expression was detected
at birth and active throughout the postnatal period. Despite early
transgene expression around birth, body weight gain was reduced only at
an age later than 3 wk postnatally (Fig. 1
). We have demonstrated high endogenous IGFBP-2 expression during the
early postnatal period in nontransgenic controls, suggesting absence of
a clear phenotype due to minor differences of IGFBP-2 serum levels.
Adult IGFBP-2 transgenic mice displayed ~10–13% reduced body weight
(Fig. 1)
, which again represents an inverse phenotype to IGF-I
transgenic mice. In pancreas, transgene expression was highest and
restricted to the islets but absent in the exocrine pancreas
(Fig. 2
). The immunohistochemical staining pattern within the islets suggested
ß cell-specific transgene expression. This finding is particularly
interesting with respect to potential actions of IGFBP-2 in glucose
homeostasis. Indeed, involvement of IGFBP-2 with glucose homeostasis
cannot be excluded, since glucose levels were reduced in IGFBP-2
transgenic mice with borderline significance (P=0.06) if
compared to nontransgenic mice (54)
. This supports the
concept that there are distinct functions for different IGFBPs, since
IGFBP-1 transgenic mice were hyperglycemic whereas IGFBP-2 transgenic
mice certainly were not. However, the potential involvement of IGFBP-2
with glucose homeostasis deserves further investigation. Taking into
account diverse phenotypes in many parameters, it is tempting to
speculate that IGFBP-2 acts mainly by an inhibition of IGF-I
bioactivity in IGFBP-2 transgenic mice.
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IGFBP-3 |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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. The concentration of IGFBP-3
in serum exceeds that of other IGFBPs by severalfold. Consistent with
its function as a carrier of IGFs in the circulation, the affinity of
IGFBP-3 for the IGFs is higher than those of most other serum IGFBPs.
The interaction with IGFs may result in inhibitory and stimulatory
responses (91)
. In addition, IGFBP-3 may exert growth
regulatory effects that occur independently of IGFs (92
, 93)
.
Two different IGFBP-3 transgenic mouse models have been established. In
one model, hIGFBP-3 is expressed under the control of the MT promoter
(Table 2
; 55
). Transgene expression was consistently found
in kidney and to a lower extent in small and large intestine.
Surprisingly, both transgenic lines showed selective organomegaly that
developed at places different from the major expression sites. Weights
of spleen, liver, and heart were significantly increased in transgenic
animals, the effect being most prominent in spleen (two- to fourfold).
Serum of transgenic animals contained immunoreactive IGFBP-3 in lower
molecular mass fractions (30–75 kDa). This nonternary IGFBP-3 might
account for the phenotype in these organs.
In the second model, the hIGFBP-3 cDNA was placed under the control of
the whey acidic protein promoter (Table 2
; 56
), which
directs expression of the transgene to mammary tissue during late
pregnancy and throughout lactation. In situ hybridization
showed transgene expression in epithelial cells of alveoli and ducts
and confirmed its absence in myoepithelial and stromal cells of mammary
tissue. Despite high transgene expression, no abnormalities were
obvious in mammary development during pregnancy. The only structural
difference was an overall reduced size of alveoli in transgenic
animals. However, the involution of the mammary gland after pregnancy
was altered. The remodeling of mammary tissue was retarded in IGFBP-3
transgenic animals possibly as a consequence of decreased apoptosis.
IGFBP-3 might exert this effect directly in an IGF-independent manner.
Alternatively, IGFBP-3 might direct IGF-I, which is known to have
antiapoptotic properties (94)
.
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IGFBP-4 |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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. It exists as a 24 kDa nonglycosylated and a 28 kDa
N-glycosylated protein (Table 1)
. During embryonic development, IGFBP-4
is expressed in the zone of polarizing activity of the developing limb
bud. It is also detected in the vicinity of precartilage elements, and
it is speculated that IGFBP-4 expression in interdigital tissue might
counteract the antiapoptotic effect of IGF-I (96)
. In
adult murine tissues, IGFBP-4 is found most abundantly in liver,
kidney, and spleen and to a lesser extent in lung, heart, brain, and
muscle (Table 1)
. In the adult skeleton, IGFBP-4 is a major player of
bone formation and resorption (97)
. In vitro
IGFBP-4 has consistently been shown to inhibit IGF-I- and
IGF-II-mediated actions (29
, 98
99
100
101)
.
Only very recently the first transgenic mouse strain was published in
which rIGFBP-4 expression is driven by two different promoter
constructs (Table 2
; 57
). The first construct consisting
of 724 bp of the mouse smooth muscle -actin promoter (SMP), followed
by the rIGFBP-4 cDNA and SV40 small T intron, enhanced IGFBP-4
expression only moderately and was not specifically targeted to smooth
muscle cell (SMC) tissues. In an alternative approach, an extended
fragment of the 5'-flanking region and the 2.5 kb intron 1 of the SM
-actin gene were placed upstream of the rIGFBP-4 cDNA. This new
construct (SMP8-IGFBP-4) contains further motifs that are in favor of
high SMC-specific expression (102)
. Transgenic animals
showed targeted expression of rIGFBP-4 in SMC-rich tissues, being
highest in bladder and aorta whereas transgene expression was lower in
stomach and in uterus. Western blotting proved the more abundant
presence of glycosylated and unglycosylated forms of IGFBP-4 in
SMC-rich tissues. However, this locally increased biosynthesis was not
accompanied by a rise in serum IGFBP-4 levels. Whereas total body
weight was indistinguishable from that of control animals, wet weights
of bladder, aorta, and stomach were significantly decreased as a
consequence of hypoplasia in SMC tissues. Transgenic mice that
overexpress IGF-I under the control of the same promoter (SMP8-IGF-I)
exhibit a hypertrophy in SMC tissue (103)
. However, this
hypertrophic reaction was only modestly decreased in IGF-I/IGFBP-4
double transgenic animals. In addition, the decrease of SMC mass in
SMP8-IGFBP-4 transgenic occurred without interference with IGF-I
abundance or gene expression (57)
. One might speculate
that the inhibitory action of IGFBP-4 might occur through
IGF-independent mechanisms, though a satisfactory explanation for this
surprising finding is still pending. Alternatively, the activation of
an IGF-I dependent SMC-derived IGFBP-4 protease (104)
might account for these results. In marked contrast to in
vitro experiments and the overexpression of IGFBP-4 in SMC are
preliminary results of IGFBP-4 knockout mice: homozygous mutants are
clearly smaller than wild-type littermates, supporting the idea that
IGFBP-4 may be required for optimal action of IGF-II in vivo
rather than act as an inhibitor (45)
.
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IGFBP-5 |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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.
Furthermore, it is involved in the regulation of several physiological
processes in ovary and kidney (27)
. Recently, IGFBP-5 was
also identified as one component of a ternary complex with IGF-I or -II
and ALS in the human circulation (106)
. This finding
requires a re-evaluation of the role of this IGFBP in regulating both
systemic and local IGF actions. Despite these unique characteristics,
no transgenic models that overexpress IGFBP-5 have been reported so
far. We have generated two independent transgenic lines that have
stably integrated the murine IGFBP-5 cDNA under the control of the CMV
promoter (Fig. 3
). Preliminary examinations revealed limited expression of the transgene
in some organs (M. R. Schneider et al., unpublished results). If
these animals show consistent overexpression of the transgene in
certain tissues, they should provide powerful models to elucidate
regulatory and developmental properties of IGFBP-5 in vivo.
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IGFBP-6 |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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, 108)
.
During mouse development, strong IGFBP-6 immunoreactivity was found in
ossifying bones of the cranial base, in cell clusters of the pancreas
anlage, in the trigeminal ganglion, in myoblasts, and in motoneurons of
the spinal cord. In tissues of adult mice, strong IGFBP-6
immunostaining was present in epidermal and peridermal layers of the
skin, in meningeal layers, in long-striated skeletal muscle, and in the
Langerhans islets of the pancreas (Table 1
; 109
). IGFBP-6
expression is markedly up-regulated in pancreatic tumors of
SV40-transgenic mice re-expressing IGF-II (T. Braulke, personal
communication). However, mice lacking both IGF-II and IGF-II-R
expression also show strong IGFBP-6 immunoreactivity in all pancreatic
islet cells, secretory granules of acinar cells, and interlobar
connective tissue of exocrine pancreas (110)
. IGFBP-6
knockout mice do not appear to differ significantly from control
animals (45)
, and to date no IGFBP-6 transgenic mouse
model exists. Thus, the role of IGFBP-6 in vivo remains
unclear and must be the subject of future studies. |
CONCLUSIONS AND PERSPECTIVES FOR FUTURE RESEARCH |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONIGFBP-1IGFBP-2IGFBP-3IGFBP-4IGFBP-5IGFBP-6CONCLUSIONS AND PERSPECTIVES FOR...REFERENCES |
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-actin-IGFBP-4 fusion gene induces smooth muscle hypoplasia. Endocrinology 139,2605-2614-actin gene contains evolutionarily conserved sequence motifs within a functional promoter. J. Biol. Chem. 265,16667-16675This article has been cited by other articles:
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  O. Escribano, C. Guillen, C. Nevado, A. Gomez-Hernandez, C. R. Kahn, and M. Benito {beta}-Cell Hyperplasia Induced by Hepatic Insulin Resistance: Role of a Liver-Pancreas Endocrine Axis Through Insulin Receptor A Isoform Diabetes, April 1, 2009; 58(4): 820 - 828. [Abstract] [Full Text] [PDF]
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 S. Yakar, C. J. Rosen, M. L. Bouxsein, H. Sun, W. Mejia, Y. Kawashima, Y. Wu, K. Emerton, V. Williams, K. Jepsen, et al. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism FASEB J, March 1, 2009; 23(3): 709 - 719. [Abstract] [Full Text] [PDF]
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 M. I. Lewis, M. Fournier, T. W. Storer, S. Bhasin, J. Porszasz, S.-G. Ren, X. Da, and R. Casaburi Skeletal muscle adaptations to testosterone and resistance training in men with COPD J Appl Physiol, October 1, 2007; 103(4): 1299 - 1310. [Abstract] [Full Text] [PDF]
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 P. Saenger, P. Czernichow, I. Hughes, and E. O. Reiter Small for Gestational Age: Short Stature and Beyond Endocr. Rev., April 1, 2007; 28(2): 219 - 251. [Abstract] [Full Text] [PDF]
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 Y. Ning, A. G. P. Schuller, S. Bradshaw, P. Rotwein, T. Ludwig, J. Frystyk, and J. E. Pintar Diminished Growth and Enhanced Glucose Metabolism in Triple Knockout Mice Containing Mutations of Insulin-Like Growth Factor Binding Protein-3, -4, and -5 Mol. Endocrinol., September 1, 2006; 20(9): 2173 - 2186. [Abstract] [Full Text] [PDF]
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 V. Shukla, X. Coumoul, L. Cao, R.-H. Wang, C. Xiao, X. Xu, S. Ando, S. Yakar, D. LeRoith, and C. Deng Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. Cancer Res., July 15, 2006; 66(14): 7151 - 7157. [Abstract] [Full Text] [PDF]
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 J. K. Christians, A. Hoeflich, and P. D. Keightley PAPPA2, an Enzyme That Cleaves an Insulin-Like Growth-Factor-Binding Protein, Is a Candidate Gene for a Quantitative Trait Locus Affecting Body Size in Mice Genetics, July 1, 2006; 173(3): 1547 - 1553. [Abstract] [Full Text] [PDF]
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 Z. Hu, Z. Zhang, J. W. Kim, Y. Huang, and T. J. Liang Altered Proteolysis and Global Gene Expression in Hepatitis B Virus X Transgenic Mouse Liver J. Virol., February 1, 2006; 80(3): 1405 - 1413. [Abstract] [Full Text] [PDF]
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 C. Mantey, G. A. Brockmann, E. Kalm, and N. Reinsch Mapping and Exclusion Mapping of Genomic Imprinting Effects in Mouse F2 Families J. Hered., July 1, 2005; 96(4): 329 - 338. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]
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 A. Marchand, C. Tomkiewicz, J.-P. Marchandeau, E. Boitier, R. Barouki, and M. Garlatti 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Insulin-Like Growth Factor Binding Protein-1 Gene Expression and Counteracts the Negative Effect of Insulin Mol. Pharmacol., February 1, 2005; 67(2): 444 - 452. [Abstract] [Full Text] [PDF]
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 V. Chandrashekar, D. Zaczek, and A. Bartke The Consequences of Altered Somatotropic System on Reproduction Biol Reprod, July 1, 2004; 71(1): 17 - 27. [Abstract] [Full Text] [PDF]
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 G. Bienvenu, D. Seurin, P. Grellier, P. Froment, M. Baudrimont, P. Monget, Y. Le Bouc, and S. Babajko Insulin-Like Growth Factor Binding Protein-6 Transgenic Mice: Postnatal Growth, Brain Development, and Reproduction Abnormalities Endocrinology, May 1, 2004; 145(5): 2412 - 2420. [Abstract] [Full Text] [PDF]
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P. Froment, C. Staub, S. Hembert, C. Pisselet, M. Magistrini, B. Delaleu, D. Seurin, J. E. Levine, L. Johnson, M. Binoux, et al. Reproductive Abnormalities in Human Insulin-Like Growth Factor-Binding Protein-1 Transgenic Male Mice Endocrinology, April 1, 2004; 145(4): 2080 - 2091. [Abstract] [Full Text] [PDF]
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 P. Delafontaine, Y.-H. Song, and Y. Li Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 435 - 444. [Abstract] [Full Text]
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 J A Mohammed, A Y. Mok, A Parbtani, and D G Matsell Increased expression of insulin-like growth factors in progressive glomerulonephritis of the MRL lpr mouse Lupus, August 1, 2003; 12(8): 584 - 590. [Abstract] [PDF]
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 E. Conti, D. Pitocco, E. Capoluongo, C. Zuppi, G. Ghirlanda, F. Crea, and F. Andreotti IGF-1 and Macrovascular Complications of Diabetes: Alternative interpretations of recently published data Diabetes Care, May 1, 2003; 26(5): 1653 - 1654. [Full Text] [PDF]
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 I. Foucher, M. Volovitch, M. Frain, J. J. Kim, J.-C. Souberbielle, L. Gan, T. G. Unterman, A. Prochiantz, and A. Trembleau Hoxa5 overexpression correlates with IGFBP1 upregulation and postnatal dwarfism: evidence for an interaction between Hoxa5 and Forkhead box transcription factors Development, September 1, 2002; 129(17): 4065 - 4074. [Abstract] [Full Text] [PDF]
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 M. S. Sandhu, D. B. Dunger, and E. L. Giovannucci Insulin, Insulin-Like Growth Factor-I (IGF-I), IGF Binding Proteins, Their Biologic Interactions, and Colorectal Cancer J Natl Cancer Inst, July 3, 2002; 94(13): 972 - 980. [Abstract] [Full Text] [PDF]
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P. Froment, D. Seurin, S. Hembert, J. E. Levine, C. Pisselet, D. Monniaux, M. Binoux, and P. Monget Reproductive Abnormalities in Human IGF Binding Protein-1 Transgenic Female Mice Endocrinology, May 1, 2002; 143(5): 1801 - 1808. [Abstract] [Full Text] [PDF]
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A. Hoeflich, R. Reisinger, H. Lahm, W. Kiess, W. F. Blum, H. J. Kolb, M. M. Weber, and E. Wolf Insulin-like Growth Factor-binding Protein 2 in Tumorigenesis: Protector or Promoter? Cancer Res., December 1, 2001; 61(24): 8601 - 8610. [Full Text] [PDF]
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E. P. Smith, A. Kamyar, W. Niu, J. Wang, B. Cercek, S. D. Chernausek, and J. A. Fagin IGF-Binding Protein-4 Expression and IGF-Binding Protein-4 Protease Activity Are Regulated Coordinately in Smooth Muscle During Postnatal Development and After Vascular Injury Endocrinology, October 1, 2001; 142(10): 4420 - 4427. [Abstract] [Full Text] [PDF]
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K. M. Jervis and B. Robaire Dynamic Changes in Gene Expression along the Rat Epididymis Biol Reprod, September 1, 2001; 65(3): 696 - 703. [Abstract] [Full Text] [PDF]
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 Z. Fu, T. Noguchi, and H. Kato Differential regulation of IGFBP-2 and IGFBP-5 gene expression by vitamin A status in Japanese quail Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E138 - E146. [Abstract] [Full Text] [PDF]
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A. Hoeflich, S. Nedbal, W. F. Blum, M. Erhard, H. Lahm, G. Brem, H. J. Kolb, R. Wanke, and E. Wolf Growth Inhibition in Giant Growth Hormone Transgenic Mice by Overexpression of Insulin-Like Growth Factor-Binding Protein-2 Endocrinology, May 1, 2001; 142(5): 1889 - 1898. [Abstract] [Full Text]
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K. Prelle, M. Stojkovic, K. Boxhammer, J. Motlik, D. Ewald, G. J. Arnold, and E. Wolf Insulin-Like Growth Factor I (IGF-I) and Long R3IGF-I Differently Affect Development and Messenger Ribonucleic Acid Abundance for IGF-Binding Proteins and Type I IGF Receptors in in Vitro Produced Bovine Embryos Endocrinology, March 1, 2001; 142(3): 1309 - 1316. [Abstract] [Full Text] [PDF]
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 S.-Y. Chan and R. W.-C. Wong Expression of Epidermal Growth Factor in Transgenic Mice Causes Growth Retardation J. Biol. Chem., December 1, 2000; 275(49): 38693 - 38698. [Abstract] [Full Text] [PDF]
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