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Nutritional Sciences Program, University of Missouri, Columbia, MO 65211
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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KEY WORDS: • zinc • cell proliferation • IGF-I • growth hormone • DNA synthesis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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), the first limiting role of zinc in growth has not been
defined. Reduced food intake occurs within 4–5 d of feeding a
zinc-depleted diet to rats (Giugliano and Millward 1984
), hence an energy deficit could explain the impairment in
growth. However, force-feeding a zinc-depleted diet to rats
failed to correct growth and exacerbated the clinical symptoms of the
deficiency (Park et al. 1986
). When zinc is inadequate
to maintain growth or cellular metabolism, reduced food intake may be a
protective mechanism to allow survival. The failure to correct growth
with increased food intake suggests that growth is the first limiting
role for zinc. Growth occurs through cell division and requires DNA,
RNA and protein synthesis. Zinc participates in a wide variety of
cellular processes as a cofactor for many enzymes and influences gene
expression through transcription factors (Wu and Wu 1987
). Growth is regulated hormonally by several systems, but
the main influence on somatic growth is provided by growth hormone
(GH)3
and insulin-like growth factor-I (IGF-I).
GH and IGF-I are affected by zinc deficiency, but these changes do
not fully explain the growth inhibition. Zinc may also affect mitogenic
hormone signal pathways that specifically direct cell proliferation.
Figure 1
illustrates the relationships among these events. This review
summarizes the role of zinc in DNA replication, hormone directed cell
division and mitogenic signal pathways.
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Zinc in DNA replication |
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TOPABSTRACTINTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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). A direct role for zinc in DNA and protein synthesis is
also evident. Zinc is present in the cell nucleus, nucleolus and
chromosomes, and zinc stabilizes the structure of DNA, RNA and
ribosomes (Wu and Wu, 1987
). Numerous enzymes associated
with DNA and RNA synthesis are also zinc metalloenzymes, including RNA
polymerase (Wu et al. 1992
), reverse transcriptases and
transcription factor IIIA (Wu and Wu 1987
). The zinc in
these enzymes is tightly bound and forms a variety of structures that
are functionally important to the enzyme (Chesters 1991
). One common structure is the zinc finger domains in which
the zinc ion forms a loop in the polypeptide chain by creating a bridge
between cysteine and histidine residues. Many proteins containing zinc
fingers have been discovered, with this motif being one of three
considered fundamental for eukaryotic regulatory proteins to bind
specific DNA sequences (Vallee and Auld 1995
).
Bunce (1994
) recently reviewed the relationships among
the clinical effects of zinc deficiency on embyrogenesis, growth and
differentiation and regulation of the nuclear hormone receptor
superfamily. Because these receptors are regulated by zinc finger
domains, limited zinc availability may impair their responsiveness and
thereby explain the reproductive effects of zinc deficiency. It appears
likely that transcription factor control of gene expression is a site
for zinc regulation. However, further characterization of these
relationships will require a more thorough understanding of the changes
in zinc flux and distribution within the cell nucleus.
During the first 5 d of feeding a zinc-deficient diet to rats,
a linear decrease in thymidine incorporation into DNA was observed in
liver, kidney spleen and testes (Williams and Chesters 1970
). Thymidine kinase catalyzes the phosphorylation of
deoxythymidine to deoxythymidine monophosphate in the
pyrimidine salvage pathway. The activity of thymidine kinase
increases dramatically during G1 and early S
phases of the cell cycle and is often used as a marker of cell
proliferation. The decrease in thymidine kinase occurred before a
decline in food intake or body weight and therefore was not associated
with decreased nutrient availability. After 11 d of feeding the
deficient diet, less total DNA was present in liver and kidney compared
with controls. An explanation for the apparent decrease in DNA
synthesis was thought to be due to reduced thymidine kinase activity
(Chesters et al. 1990
). Thymidine kinase is not a zinc
metalloenzyme, but the transcription of the enzyme appears to be
regulated by zinc availability. In Swiss 3T3 cells, sequestering zinc
by addition of the chelator diethylenetriaminepentaacetic acid (DTPA)
resulted in decreased thymidine kinase mRNA (Chesters et al. 1990
). The inhibition was reversed by adding zinc and iron, but
not iron alone, with the chelator. Zinc appears to regulate thymidine
kinase mRNA through zinc-dependent protein binding to the promoter
region of the gene (Chesters et al. 1995
). The role of
zinc appears to be through regulation of thymidine kinase
transcription, and not mRNA stability (Prasad et al. 1996
). The decreased thymidine mRNA observed in cells incubated
with DTPA did not fully explain the decrease in thymidine
incorporation. When cells were transfected with an SV40 thymidine
kinase construct, the addition of DTPA did not decrease thymidine
kinase mRNA, but thymidine incorporation was inhibited (Chesters et al. 1993
). Therefore, decreased thymidine kinase mRNA was
not sufficient to explain inhibition of DNA synthesis in the absence of
zinc. The authors proposed that zinc was required for two distinct
steps in the sequence of events that induce DNA synthesis. First, zinc
affected the entry of cells into S phase, and second, zinc influenced
thymidine kinase mRNA. The mechanism by which zinc affects entry of
cells into S phase has not been defined.
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Zinc and growth hormone |
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TOPABSTRACTINTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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). As the pituitary is the source of GH, a primary
endocrine regulator of somatic growth, several studies have
investigated the role of GH in the inhibition of growth due to zinc
deficiency. Zinc deficiency caused failure of GH secretion from the
pituitary (Root et al. 1979
), and circulating GH
concentrations are decreased by zinc deficiency in rats (Roth and Kirchgessner 1997
). The level of GH in the blood of rats
fed a zinc-deficient diet or pair-fed for 2 d was lower
than zinc-adequate controls (Roth and Kirchgessner 1997
). In zinc-depleted rats, GH levels remained constant
through d 32, but between d 2 and 7, GH increased in the pair-fed
rats and remained similar to that in zinc-adequate rats throughout
the study period (Fig. 2
). The concentration of GH in the pituitary was significantly increased
in both the pair-fed and zinc-depleted animals compared with
the zinc-adequate rats on d 22 and 32. An explanation for the
elevation of pituitary GH is not readily evident, because both normal
and decreased blood levels of GH (pair-fed and zinc-depleted,
respectively) were observed. Pituitary release of GH in response to
GH-releasing factor was not different between zinc-adequate and
deficient rats (Dorup et al. 1991
), which indicated that
the GH secretory pathway in the pituitary was functional in
zinc-deficient rats.
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) administered bovine GH (40 µg/d)
by subcutaneous injection for 2 wk to rats that had previously been fed
a zinc-depleted diet for 3 wk and found no stimulation of growth
compared with rats not fed GH. A small increase in growth occurred in
hypophysectomized rats fed the zinc-depleted diet when treated with
GH, but the increase was much less than that induced by zinc. A smaller
dose of bovine GH (20 µg/d) administered for 3 wk was also
ineffective in stimulating growth in zinc-depleted rats
(Oner et al. 1984
). Similarly, human GH (20 µg/d)
administered to rats fed a zinc-deficient diet failed to stimulate
growth (Dicks et al. 1993
). Hence, the administration of
exogenous GH to zinc-depleted rats was insufficient to overcome the
growth inhibition, despite an increase in circulating GH levels (1.0
and 2.7 ng/mL in vehicle and growth hormone–treated animals,
respectively). It is also of interest that the response to GH in
zinc-deficient rats and rats pair-fed a zinc-adequate diet
was similar in these studies, that is, growth was not stimulated in
either group by GH. Because GH administration did not increase food
intake in the zinc-deficient animals (Dicks et al. 1993
), the overall failure to stimulate growth may have been
due to inadequate dietary intake. Perhaps GH could not induce growth
due to an energy deficiency.
A primary target for GH action is bone (Ohlsson et al. 1998
). To determine whether bone growth in zinc-deficient
rats was responsive to GH, Cha and Rojhani (1997
)
implanted miniosmotic pumps containing GH in the hindlimb of
hypophysectomized rats. GH stimulated tibial-epiphyseal cartilage
width in zinc-adequate or pair-fed rats but not in
zinc-deficient rats. Bone growth in zinc-deficient rats was
therefore resistant to GH. GH stimulates the secretion of IGF-I
from the liver, and IGF-I is thought to mediate part of the
somatogenic activity of GH in bone (Ohlsson et al. 1998
). The GH administered to the zinc-depleted rats failed
to increase circulating IGF-I concentrations (Dicks et al. 1993
, Oner et al. 1984
), which may explain the
failure to stimulate growth. Zinc potentiates the action of IGF-I
(Matsui and Yamaguchi 1995
) and increases endogenous
IGF-I synthesis (Yamaguchi and Hashizume 1994
) in
cultured bone cells. Therefore, failure of GH to stimulate bone growth
in zinc-deficient animals may have been due to limited zinc
availability in the bone cells, independent of their IGF-I or GH
status.
Growth hormone contains a zinc-binding site that is structurally
and functionally important (Cunningham et al. 1991
). At
concentrations of zinc greater than micromolar, zinc promotes the
formation of a GH dimer. The high concentrations of zinc in the
pituitary, therefore, may provide for formation of dimerized GH, which
is less susceptible to degradation. Dimerized GH has a low affinity for
GH receptors, so the presence of high concentrations of zinc in
pituitary secretions may prevent the association of GH with cellular
receptors proximal to the pituitary. This may be necessary to ensure GH
reaches receptors in the periphery. The binding of GH to the prolactin
receptor, but not to the GH receptor, requires zinc (Cunningham et al. 1990
). The presence of 50 µmol/L zinc resulted in an
8000-fold increase in binding affinity of GH to the prolactin receptor.
In contrast, these concentrations of zinc slightly inhibited GH binding
to the GH receptor. Because prolactin receptors mediate lactogenic
responses and GH receptors mediate somatogenic responses, the
dependence of prolactin receptors on zinc does not fully correlate with
the observed growth inhibition of zinc-deficient animals. However,
GH and prolactin receptors belong to the cytokine superfamily of
receptors (Cunningham et al. 1990
), so future work may
demonstrate other roles for zinc in mediating the activity of these
hormones.
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Zinc and insulin-like growth factor-I |
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TOPABSTRACTINTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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). On activation of the
receptor by IGF-I, a cascade of phosphorylations occurs within the
cell that mediate the cellular responses. Insulin-like growth
factor-I associates with IGF binding proteins in the circulation;
at least eight distinct binding proteins have been identified thus far
(Rajaram et al. 1997
). There is increasing evidence that
IGF binding proteins are not inert carrier proteins but rather form a
complex system for regulating the availability of IGF-I to cells.
Circulating levels of IGF-I are readily influenced by nutritional
status (Underwood 1996
). Specifically, decreased serum
IGF-I occurs in humans and animals when dietary energy or protein
intake is inadequate. In humans, zinc deficiency decreased circulating
IGF-I concentrations independently of total energy intake
(Cossack 1991
). Serum IGF-I was lower in rats fed a
zinc-deficient diet for 2 wk compared with zinc-adequate
controls (Bolze et al. 1987
, Cossack 1984
, Dorup et al. 1991
), and the decrease in
IGF-I corresponded to a decrease in serum zinc (Dorup et al. 1991
). Furthermore, tibial zinc concentration, which is a
sensitive measure of zinc status, was positively correlated with serum
IGF-I concentration (Cossack 1984
). The decreased
concentration of IGF-I in the serum of zinc-depleted rats was
not corrected by a high protein diet, but the addition of zinc to a low
protein diet increased serum IGF-I (Cossack, 1986
).
Total nutrient intake clearly influences serum IGF-I concentrations
in the short term, as a linear decrease in plasma IGF-I occurred in
rats fasted for 72 h (Cossack 1988
). Refeeding
initiated almost complete recovery of plasma IGF-I levels within
48 h, even if the refeeding diet lacked adequate zinc. However,
plasma IGF-I levels continued to increase only in rats fed diets
containing 90 or 140 mg/kg zinc. When the refeeding diet contained 30
mg/kg zinc, plasma IGF-I decreased after 72 h and had returned
to the fasting level by 192 h.
The anorexia, and subsequent decreased energy intake, associated with
feeding a zinc-depleted diet may be the cause of decreased serum
IGF-I. In some studies, serum IGF-I levels in zinc-depleted
and pair-fed rats were not different from each other but were lower
compared with those of zinc-adequate ad libitum–fed rats
(Bolze et al. 1987
, Clegg et al. 1995
).
Roth and Kirchgessner (1997
) measured IGF-I levels
periodically for 32 d in rats fed a zinc-adequate diet ad
libitum or pair-fed or rats fed a zinc-deficient diet ad
libitum (Fig. 3
). Serum IGF-I increased in the zinc-adequate ad libitum–fed
rats during the study at a faster rate than in either the pair-fed
or zinc-depleted rats. However, there was no difference between the
pair-fed and zinc-depleted rats until d 32. To determine
whether zinc exerted an effect on plasma IGF-I that was independent
of food intake, Roth and Kirchgessner (1994
) maintained
food intake by intragastric feeding. Force-feeding a
zinc-depleted diet to rats for 14 d resulted in a 28%
decrease in serum IGF-I compared with rats fed a zinc-adequate
diet, although food intake was similar. Hence, in the absence of
adequate zinc, serum IGF-I concentrations are not maintained even
when energy intake is adequate.
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). The first technique was to implant miniosmotic pumps
containing IGF-I or vehicle intraperitoneally into immature, male
Wistar rats. After recovery from the surgery, the rats were divided
into two groups and fed either a zinc-adequate or a
zinc-deficient diet. Body weight gain was significantly less after
d 8 in rats fed the zinc-deficient compared with those fed the
zinc-adequate diet, but the administration of IGF-I did not
affect growth in either diet group (Fig. 4
). After 8 d, serum IGF-I levels were similar in the
zinc-depleted rats treated with IGF-I and the zinc-adequate
rats not treated with IGF-I. Insulin-like growth factor-I
levels in zinc-depleted rats not treated with IGF-I were
significantly lower than those of any other treatment group.
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). After 8 d, serum IGF-I levels were similar in
the zinc-depleted, megestrol acetate–treated rats compared with
the zinc-adequate rats (Fig. 5
). However, although food intake and serum IGF-I levels were
maintained, growth inhibition persisted in the zinc-deficient rats.
These findings suggest that maintaining serum IGF-I or food intake,
or both, in zinc-deficient rats is not sufficient to correct the
growth inhibition associated with zinc deficiency.
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). Force-feeding a zinc-deficient
diet resulted in increased serum GH but decreased IGF-I
concentrations compared with zinc-adequate controls. The refractory
response to GH induced by force-feeding or exogenous administration
(Dicks et al. 1993
, Oner et al. 1984
)
suggests a lack of hepatic response to GH. Hepatic GH receptor and GH
binding protein, as well as IGF-I mRNA, were lower in rats fed a
zinc-deficient diet compared with pair-fed or zinc-adequate
control rats (McNall et al. 1995
). A decrease in serum
and liver GH binding and hepatic GH receptor and GH binding protein
mRNA has also been observed in rats fed a zinc-deficient diet for
30 d (Ninh et al. 1995
). The decreased GH binding
was associated with decreased serum IGF-I and hepatic IGF-I
mRNA. The decreases in mRNA were not due to overall decreased gene
transcription associated with reduced energy intake, because all values
were lower than those in pair-fed controls. These findings suggest
that GH regulation of hepatic IGF-I production is impaired in
zinc-depleted animals, at the level of the GH receptor. As
discussed earlier, numerous zinc finger–containing transcription
factors have been identified; hence, regulation of specific genes may
be influenced by zinc availability.
The evidence reviewed demonstrates that zinc deficiency in the rat is
characterized by decreased food intake, decreased growth, low
circulating levels of GH and IGF-I, decreased hepatic production of
IGF-I, GH receptor and GH binding protein and unresponsiveness to
exogenous GH (Fig. 6
). Several lines of evidence suggest that decreased hepatic production
of IGF-I due to failure to respond to GH explains the growth
failure observed in zinc deficiency. However, maintaining serum
IGF-I levels by exogenous administration or by inducing food intake
(Browning et al. 1998
) in zinc-deficient rats does
not correct the growth inhibition. Therefore, changes in the GH-IGF
axis alone cannot explain the growth inhibition observed in zinc
deficiency. Hence, zinc is required for some aspect of growth
regulation at the cellular level that is independent of the effects
observed on circulating IGF-I and GH.
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Zinc regulation of DNA synthesis in cultured cells |
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TOPABSTRACTINTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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) hypothesized that zinc was required for the
accumulation and maintenance of a protein that mediated the entry of
cells into S phase. It was found that zinc was required between 6 and
13 h after the stimulation of cells from quiescence, which
corresponded with the mid-to-late G1 phase
(Chesters et al. 1989
). Activation of the IGF-I
receptor has been proposed to be the restriction point of the
G1-to-S phase transition (Campisi and Pardee 1984
). Hence, an alternative explanation for the
requirement for zinc in DNA synthesis would be that zinc is required
for IGF-I mediation of the G1-to-S phase
transition. To investigate the role of zinc in IGF-I regulation of
cell division, we used the cell culture model developed and
characterized by Chesters et al. (1989
). Swiss 3T3 cells
were seeded onto culture dishes in complete medium [Dulbecco’s
modified Eagle’s medium (DMEM) with 10% fetal bovine serum)
and allowed to grow for 3 d. The medium was then replaced with
DMEM containing 2% serum for 2 d to induce quiescence. Cell
division was stimulated by incubating the cells overnight with medium
containing 10% serum. To investigate the role of zinc, DTPA (600 µM)
with or without zinc (400 µM) was added to the stimulating medium.
Radiolabeled thymidine incorporation (4-h uptake) was measured as a
marker of DNA synthesis and cell division. Using this model, we
verified that DTPA inhibited thymidine uptake, and adding zinc with
DTPA restored thymidine uptake to control levels (MacDonald et al. 1998
). The response to zinc was specific, because adding
calcium, iron or cadmium with DTPA did not increase thymidine uptake.
In 3T3 cells incubated with DTPA, radiolabeled IGF-I receptor
binding was slightly decreased compared with incubation with DTPA plus
zinc, as determined by Scatchard analysis of displacement data
(Fig. 7
). Although this finding was consistent, the decrease in binding of
cells was not sufficient to explain the inhibition of thymidine uptake
observed in cells incubated with DTPA. Furthermore, using an
immunocytochemical technique and flow cytometry to quantify receptor
number per cell, we found no significant change in receptor number when
cells were incubated with DTPA compared with DTPA plus zinc
(Thornton et al. 1998
). The binding experiments were
performed using radiolabeled IGF-I as the ligand, displaced by
unlabeled IGF-I to determine specific IGF-I binding to the
cells. Recent evidence suggests that IGF-I availability for binding
to surface receptors is mediated by the presence of IGF binding
proteins (Rajaram et al. 1997
). Because radiolabeled
IGF-I binds to both receptor and binding proteins, we speculated
that changes in IGF binding proteins might be occurring in
zinc-depleted cells that affected the IGF-I binding results.
Using Western immunoblotting, we found a significant increase in IGF
binding protein-3 concentration in 3T3 cells incubated with DTPA
compared with DTPA plus zinc or control cultures (Fig. 8A
). Hence, increased IGF binding protein-3 in cells incubated with DTPA
would perhaps sequester IGF-I and render it unavailable to bind,
and hence activate, the membrane receptor. Blocking IGF binding
protein-3 with an antibody resulted in significantly greater IGF-I
stimulation of thymidine uptake compared with cells incubated without
the antibody (Fig. 8B
), indicating IGF binding
protein-3 sequestered IGF-I and reduced the IGF-I–IGF-I receptor
interaction. Based on these results and additional evidence from
experiments using des(1-3)IGF-I (which has weak binding affinity to IGF
binding proteins), we conclude that IGF-I receptor number is not
affected in 3T3 cells incubated with DTPA, but an increase in IGF
binding protein-3 occurs. The increased IGF binding protein-3 may
prevent IGF-I binding to the receptor and thereby prevent
initiation of DNA synthesis.
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). Cells were treated as
described, except instead of stimulating from quiescence with DMEM and
10% fetal bovine serum, we placed the cells into serum-free medium
containing 0.1% bovine serum albumin. The cells were then sequentially
stimulated with platelet-derived growth factor (PDGF; 3 h),
epidermal growth factor (EGF; 0.5 h) and IGF-I (16 h) as
previously described (MacDonald et al. 1998
). In this
model, we added DTPA or DTPA plus zinc with the growth factors
individually and in combination and measured thymidine uptake. A
summary of these experiments is shown in Figure 9A
. Cells were stimulated with PDGF, EGF and IGF-I in medium
containing DTPA; zinc was added with the growth factor indicated. When
zinc was not added or was added with PDGF and EGF, thymidine uptake was
inhibited. Adding zinc with IGF-I or all three growth factors
resulted in significant thymidine uptake. Hence, in the absence of
zinc, IGF-I stimulation of thymidine uptake was prevented.
Furthermore, we demonstrated that the addition of zinc alone, without
growth factors, stimulates thymidine uptake slightly but less than the
response to zinc and IGF-I combined (Fig. 9B
).
These results clearly demonstrate that zinc is required for IGF-I
stimulation of thymidine uptake.
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). Intracellular
diadenosine tetraphosphate pools increase in cells in parallel with DNA
synthesis rate, and diadenosine tetraphosphate stimulates DNA synthesis
in quiescent cells. Diadenosine tetraphosphate regulation of cell
division may provide a mechanism for responding to zinc availability,
because cells incubated with EDTA failed to increase diadenosine
tetraphosphate in response to mitogenic hormones. |
Zinc and mitogen signal transduction |
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TOPABSTRACTINTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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; (De Meyts et al. 1994
). Hence, phosphorylation of the
IGF-I receptor is thought to be the earliest response to ligand
binding (Kato et al. 1993
). The first cytosolic proteins
to be activated by the IGF-I receptor tyrosine kinase are insulin
response substrates-1/2. The tyrosine phosphorylation of these proteins
initiates three distinct signaling pathways: phosphoinositol-3 kinase,
mitogen-activated protein kinase and protein kinase C.
Phosphoinositol-3 kinase is mainly thought to influence substrate
uptake and fuel metabolism in the cell, whereas mitogen-activated
protein kinase activation results in nuclear association and induction
of transcription factors that direct cell proliferation. We speculated
that failure to activate the phosphorylation cascade within cells in
response to IGF-I might occur in zinc deficiency, which would
explain the inhibition of DNA synthesis caused by zinc depletion. 3T3
cells, however, were not a useful model to study this phenomenon
because of their low receptor number. We therefore used an NIH 3T3 cell
line stably transfected with the IGF-I receptor promoter that
overexpressed the IGF-I receptor B3 cells; (Blakesley et al. 1996
). The B3 cells demonstrated decreased thymidine uptake
when incubated with DTPA, which was reversed by zinc, similar to the
Swiss 3T3 cells. By Western immunoblotting, we found IGF-I receptor
phosphorylation to be similar in cells incubated with DTPA or DTPA plus
zinc (Fig. 11
). Similarly, insulin response substrates-1/2 phosphorylation was not
affected by the zinc status of the cells. We therefore concluded that
IGF-I receptor activation, at the level of receptor and insulin
response substrates-1/2 phosphorylation, was not affected by zinc
depletion and therefore could not explain the growth inhibition. The
effects of zinc depletion on the IGF-I receptor signal cascade have
not been further characterized. However, Hansson (1996
)
observed no affect on mitogen-activated protein kinase activity in
cultured cells incubated with the chelator 1,10-phenanthroline compared
with control cells. The addition of physiological concentrations of
zinc to the cells increased mitogen-activated protein kinase
activity and induced phosphorylation of cellular proteins. The author
speculated that zinc at these high concentrations may be either a
potent activator of protein phosphorylation or an inhibitor of protein
phosphatases, which might explain the potentiation of wound healing by
zinc-containing ointments.
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). Protein kinase C is a zinc metalloenzyme (Hubbard et al. 1991
), and zinc facilitates the binding of protein
kinase C to the cytoskeleton (Forbes et al. 1990
).
However, protein kinase C activity was not affected by zinc deficiency
in rats force-fed a zinc-depleted diet compared with controls
(Kirchgessner et al. 1996
). In Balb/c 3T3 cells,
IGF-I stimulated phosphorylation of a synthetic substrate for
protein kinase C (Kojima et al. 1993
). The activation of
protein kinase C was associated with induction of cell proliferation
and was dependent on extracellular calcium. In neuronal cells
(Kleppisch et al. 1992
) and Balb/3T3 cells
(Kojima et al. 1993
), IGF-I stimulation of calcium
influx was mediated by protein kinase C. Both IGF-I (Kojima et al. 1988
) and IGF-II (Nishimoto et al. 1987
) stimulated calcium influx in primed, competent Balb/3T3
cells. For both ligands, calcium influx was essential for stimulation
of cell proliferation. We have also observed in Swiss 3T3 cells that
calcium influx is required for cell proliferation, and
IGF-I–stimulated calcium uptake requires zinc (data not shown). These
findings are in agreement with animal studies that have demonstrated
impaired calcium uptake in platelets (O’Dell and Emery 1991
) and synaptosomes (Browning and O’Dell 1994
) of zinc-deficient rats. Hence, evidence is mounting
to suggest a regulatory role for zinc in calcium-dependent
mitogenic signal transduction.
A novel zinc-binding protein, QM, was recently identified that
binds to the leucine zipper region of c-Jun (Inada et al. 1997
). The c-Jun N-terminal kinase (JNK) group of
mitogen-activated protein kinases is activated in response to
stress (Ip and Davis 1998
). This signaling pathway also
mediates the cell cycle (Pelech and Charest 1995
). In
the absence of zinc, QM failed to bind c-Jun. The binding of QM to
c-Jun was also inhibited by phosphorylation of QM by protein kinase
C. Hence, activation of protein kinase C, by IGF-I, for example,
would result in reduced QM binding to c-Jun. The implication of
these findings are that QM may be one of many transcription factors
through which zinc availability affects gene transcription. The protein
kinase C signal transduction pathway may also regulate the
transcription of metallothionein genes (Yu et al. 1997
).
The metallothionein transcriptional factor-1 binds to metal response
elements and activates metallothionein gene expression. Metallothionein
transcriptional factor-1 possesses zinc finger domains and requires
zinc for activity and therefore may serve as a sensor to regulate the
activity of the metallothionein promoter in response to zinc
concentrations. Metallothionein induction by zinc was inhibited in
Chinese hamster ovary K1 cells by protein kinase C inhibitors. The
authors speculated that protein kinase C phosphorylation of
metallothionein transcriptional factor-1 could occur within the zinc
finger domains but provided no experimental evidence to support this
hypothesis.
In conclusion, zinc deficiency results in impaired cell division that
cannot be overcome by correcting circulating mitogenic hormone
concentrations or food intake. Zinc is an essential component of
numerous metalloenzymes that direct DNA synthesis. The activity of
these enzymes is not measurably affected in early zinc deficiency,
although cell division is impaired. However, reduced zinc availability
may compromise zinc-activated gene transcription of critical
mitogenic signals (Chesters 1991
). Impaired mitogenic
hormone signal transduction may also occur, resulting in depressed cell
division. Identification of zinc-binding and transport proteins
that direct zinc distribution within the cell will be necessary to
fully understand the complex role of zinc in regulation of cell
division. Clearly, many proteins and regulatory systems are affected by
zinc, and a highly organized and coordinated process is required to
ensure survival of the animal when zinc intake is inadequate.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Missouri Agricultural Experiment Station Journal Series number 12893. Supported by the University of Missouri-Columbia Food for the 21st Century and NRICGP/USDA Grant 95–00649 and 95–37200.
3 Abbreviations used: DMEM, Dulbecco’s modified Eagle’s medium; DTPA, diethylenetriaminepentaacetic acid; EGF, epidermal growth factor; GH, growth hormone; IGF-I, insulin-like growth factor-I; PDGF, platelet-derived growth factor.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONZinc in DNA replicationZinc and growth hormoneZinc and insulin-like growth...Zinc regulation of DNA...Zinc and mitogen signal...REFERENCES |
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