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Regular Articles |
From the CRC Epithelial Biology Laboratory,*
Cell and
Tumour Biology Section, Paterson Institute for Cancer Research,
Manchester; CRC Molecular and Cellular Pharmacology
Group,
School of Biological Sciences,
University of Manchester, Manchester; and Department of
Medicine,
University of Manchester, Hope
Hospital, Salford, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have investigated the response of intestinal epithelium to ionizing
(
) radiation, in vivo. p53 protein levels are
up-regulated rapidly in response to DNA damage induced by a number of
noxious stimuli, including ionizing radiation,2
ultraviolet
irradiation,6
cytotoxic drugs,2,7
and
hypoxia.8
It has now been shown that p53 transcriptionally
regulates many genes. This regulation may either be
positive9,10
or negative.9,11
p53 has been
shown to regulate the expression of genes important for both cell cycle
arrest (an event that has been proposed to allow the cell time to
repair), such as p21WAF-1/CIP1,12,13
and apoptosis, eg, bax14-16
and
killer/DR5.17
The expression of p21WAF-1/CIP1 protein mediates p53-dependent cell cycle arrest.13,18-20 p21WAF-1/CIP1 inhibits cell cycle progression by binding to and inhibiting the function of cyclin-dependent kinases and proliferating cell nuclear antigen.21,22 In addition, p21WAF-1/CIP1 expression is associated with cell senescence.23 Loss of p21WAF-1/CIP1 function is associated with the attenuation of cell cycle arrest after DNA damage18 and with the failure of human fibroblasts to senesce in vitro.24
It has been shown previously, by ourselves and
others,25-28
that p53 protein expression in the intestinal
epithelium is increased in response to -irradiation. The acute
apoptotic response (3 to 6 hours after irradiation) observed in the
intestinal epithelium was shown to be entirely dependent on p53
expression, because it was abrogated in mice homozygously null for
p53. In addition, these studies demonstrated that at later
times after irradiation (12 to 24 hours), apoptosis could occur
independently of p53 expression.
In this paper, we have characterized the in vivo expression of p21WAF-1/CIP1 in response to ionizing radiation, using immunohistochemistry. We have contrasted the response of the different cellular hierarchies within individual intestinal crypts. The different responses observed between the epithelia of the small and large bowel have also been examined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male BDF-1 (C57BL x DBA/2) mice and male p53-wild-type (wt) and p53-null mice were bred in house. p53-wt and p53-null mice were originally obtained from Donehower et al.29 Mice were kept under a 12-hour light:12-hour dark cycle with lights on at 7:00 AM and were allowed free access to food and water. Mice used in the experiments were between 10 and 12 weeks of age.
Exposure of Animals to -Radiation
Mice were irradiated with a 137Cs source, with a dose rate of 3.8 Gy/minute. Animals were sacrificed by cervical dislocation at set times after irradiation, and the small and large bowel were removed.
Immunohistochemistry
For immunohistochemistry, tissue was fixed in 4% formaldehyde in phosphate-buffered saline (pH 7.4), before dehydration in alcohols and embedding in wax. Tissue sections were cut using a microtome at a thickness of 3 µm.
Rabbit polyclonal anti-p21WAF-1/CIP1 immunoglobulin G was obtained from Oncogene Research Products (pc55, through Amersham International, Little Chalfont, UK). Rabbit polyclonal anti-p53 immunoglobulin G (cm5) was a kind gift from Prof. D. Lane (Dundee, UK).
Immunohistochemistry was performed using biotin-conjugated goat anti-rabbit secondary antibody (Pierce and Warriner, Chester, UK), horseradish peroxidase-linked avidin-biotin complex reagents (Vector Laboratories, Peterborough, UK), and 3',3'-diaminobenzidine as the immunodetection substrate, as previously described.30
Cell Scoring
Apoptosis
Apoptotic cells, mitotic cells, and cells showing immunoreactivity
for p21WAF-1/CIP1 and p53 were scored on a cell-positional
basis within the crypts of the small and large bowel according to the
method of Ijiri and Potten.31
A minimum of 1000 cells (50
half-crypts) were counted from each mouse in every group. Apoptosis was
assessed on the evidence of morphological characteristics, such as cell
shrinkage, chromatin condensation, and margination and cellular
fragmentation.32
Mitotic cells were identified by virtue of
chromatin condensation in the absence of cytoplasmic and nuclear
shrinkage. In many mitotic cells, discrete chromosomal structure can be
observed, and in addition, mitotic cells appear horizontally displaced,
away from the other epithelial cells, toward the crypt lumen. To
determine the number of cells in S-phase of the cell cycle at given
times after the exposure to -radiation, animals were injected
intraperitoneally with 925 kBq of [3H]thymidine (248
GBq/mmol, in 0.1 ml of physiological saline) 40 minutes before
sacrifice. Tissue was then fixed in Carnoy's fixative before wax
embedding and sectioning. Tissue sections were rehydrated and coated in
K-5 nuclear track emulsion (Ilford, Cheshire, UK). After the emulsion
had dried, sections were boxed and exposed for 3 days at 4°C. Slides
were developed using Kodak D-19 developer and fixed with Hypam fixative
(Ilford). Sections were counterstained with hematoxylin before
dehydration and mounting.
Immunohistochemistry
p53 and p21WAF-1/CIP1 immunoreactivity were classified according to their intensity. Using light microscopy, it could be seen that for both p53 and p21WAF-1/CIP1, certain cells exhibited noticeably stronger immunoreactivity than the rest. These cells were classified as strongly stained. All other cells were classified together as either weakly or moderately stained. This is a fairly subjective approach; however, reproducibility of scoring was observed between mice in the same groups and was also checked using other observers.
Western Blotting
Epithelial cell preparations using a modified Weiser technique and Western blotting were carried out as previously described.30 Immunodetection was carried out using enhanced chemiluminescence (Amersham, UK). Rabbit anti-actin antibody was obtained from Sigma Chemical Co. (Poole, UK).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-radiation. The frequencies of apoptosis and
p21WAF-1/CIP1- and p53-immunoreactivity were scored for
each cell position within the intestinal crypts at given times after
irradiation. Small Intestine
Apoptosis, p53, and p21WAF-1/CIP1 Expression after 8 Gy
-Radiation
Small intestinal crypts show a characteristic peak in apoptotic
frequency at cell position 3 to 6, 4 to 48 hours after irradiation
(Figure 1
, left, solid black
line).33
Changes in p53 and p21WAF-1/CIP1
immunoreactivity were observed coincidentally with apoptosis. Neither
p53 nor p21WAF-1/CIP1 could be detected in un-irradiated
epithelium. p53 immunoreactivity was detectable 1 hour after
irradiation and p21WAF-1/CIP1 after 2 hours (data not
shown). The distribution of p53-positive cells (Figure 1
, left, shaded
line) was mainly toward the base of the small intestinal crypts
relative to the distribution of p21WAF-1/CIP1-positive
cells (Figure 1
, left, dotted line). p53 immunoreactivity was maximal
at 4 hours after irradiation, showed a gradual decline at 24 hours and
48 hours, and was almost absent by 72 hours (see Table 1
).
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The expression of both p53 and p21WAF-1/CIP1 was
subclassified as either weak/moderate or strong (Table 1)
. Data from
crypts 4 hours after exposure to ionizing radiation are shown in Figure 2
and reveal that cells with strongest
p53 immunoreactivity (Figure 2
, bold solid line) were positioned
farther toward the crypt base and that their distribution was
approximately coincident with the positional distribution of apoptotic
cells (Figure 2
, fine solid line), as previously shown by Merritt et
al.25
The majority of apoptotic cells, however, showed no
p53 immunoreactivity: this may reflect the loss or masking of
the epitope recognized by the anti-p53 antibody during apoptosis.
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shaded line) was centered toward the top of the crypt and was
approximately coincident with the distribution of
p21WAF-1/CIP1-positive cells (Figure 2
, fine dashed line).
There was no difference between the distribution of cells that were
either weakly or moderately stained for p21WAF-1/CIP1 and
that of those cells that were strongly stained for
p21WAF-1/CIP1 (data not shown). Effect of Radiation Dose on p21WAF-1/CIP1 Expression
In the small bowel, the radiation-induced increase in
p21WAF-1/CIP1 showed dose dependency. Figure 3
contrasts the response to 0.3 and 16 Gy
4 hours after exposure to -radiation. Exposure to 0.3 Gy resulted in
minimal p21WAF-1/CIP1 expression (Figure 3, a and b
, and
Table 2
). Considerable expression of
p21WAF-1/CIP1 was induced after exposure to 16 Gy, with a
greater percentage of p21WAF-1/CIP1-positive cells than was
observed after exposure to 8 Gy (39%; compare 25%: see Table 2
).
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The expression of p21WAF-1/CIP1 was confirmed to be
dependent on p53 function, as mice homozygously null for
p53 showed no radiation-induced increase in
p21WAF-1/CIP1, as detected by immunohistochemistry (Figure 4)
. The radiation-induced increase in
p21WAF-1/CIP1 was confirmed by Western blotting, which also
confirmed the absence of p21WAF-1/CIP1 up-regulation in
p53-null mice (Figure 5)
.
Control Westerns blots for actin showed comparable levels of expression
in samples from both p53-wt and p53-null mice
(data not shown). Even transfer of protein to nitrocellulose membrane
was confirmed by staining with Ponceau-S (data not shown).
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p53 and p21WAF-1/CIP1 Expression after 8 Gy
-Radiation
In the large intestinal epithelium, radiation-induced p53 and
p21WAF-1/CIP1 expression showed both spatial and temporal
differences from the small bowel (Figure 6)
. The p53 response was attenuated
(proportion of p53-positive cells per half-crypt) relative to that
observed in the small intestinal epithelium (see Tables 1 and 3
). In contrast to the small bowel,
however, the number of p53-positive cells also declined more slowly up
to 72 hours after irradiation. The p21WAF-1/CIP1 response
was of a similar magnitude to that in the small bowel up to 24 hours;
however, the frequency of p21WAF-1/CIP1 expression
gradually increased up to 72 hours and was still present up to 6 days
after irradiation. This longevity of p21WAF-1/CIP1
expression in the large bowel, relative to that observed in the small
bowel, is shown in Figure 7
.
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As in the small intestine, no p21WAF-1/CIP1 was
detected in colonic epithelial crypts 4 hours after exposure to 0.3 Gy
-radiation. Exposure to 16 Gy -radiation resulted in a large
increase in p21WAF-1/CIP1 immunoreactivity; however, in
contrast to the small bowel, exposure to 16 Gy resulted in a smaller
increase in p21WAF-1/CIP1 expression than an 8-Gy exposure
(Figure 3)
. This was an unexpected observation; however, it remains to
be determined whether this effect is demonstrated at other time points.
p21WAF-1/CIP1 Expression and [3H]Thymidine Incorporation
Incorporation of [3H]thymidine was measured to
estimate the number of cells undergoing DNA synthesis. In both the
small and large intestinal crypts exposure to -radiation severely
depressed thymidine incorporation (Figures 8 and 9)
.
There was a gradual recovery in thymidine incorporation, and by the
72-hour time point, it had returned to normal. Cells re-entering the
cell cycle (thymidine labeled) were observed at a lower position in the
crypts than the p21WAF-1/CIP1-positive cells. Positional
analysis of p21WAF-1/CIP1 immunoreactivity and
[3H]thymidine incorporation revealed that they were
almost mutually exclusive: fewer than 10% of
p21WAF-1/CIP1-positive cells at any one time demonstrated
[3H]thymidine incorporation, although the frequency of
dual-labeling cells did show a gradual time-dependent increase (Figure 8
and Tables 1 and 3
).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-radiation, with respect to expression of p53 and
p21WAF-1/CIP1, apoptosis, and inhibition of DNA synthesis.
If it is presumed that the potential for cellular damage induced by
exposure to -radiation is equivalent for all of the cells of a given
crypt, then the heterogeneous response must represent phenotypic
variations defined by the topological position of each epithelial cell
within the crypt.
Within the small intestinal epithelium, the distribution of
-radiation-induced p21WAF-1/CIP1 expression was centered
toward the top of the crypts relative to the distribution of p53 and
apoptotic cells. When the population of p53-positive cells was
subclassified as either weakly/moderately stained or strongly stained,
it was revealed that the distribution of cells strongly positive for
p53 was coincident with that for apoptosis (4 hours after exposure to 8
Gy -radiation). Previous work from this laboratory had also
identified coincidence of p53-positive cells and apoptotic cells after
irradiation at 8 Gy.25
The greater number of p53-positive
cells observed after irradiation in the current study may be explained
by a different immunostaining protocol and a different batch of cm5
antibody. Arai et al34
have also reported the positional
association of p53 expression and apoptosis. The distribution of cells
that were weakly/moderately positive for p53 was positionally
coincident with p21WAF-1/CIP1-positive cells, 4 hours after
exposure to 8 Gy -radiation. This cell population showed little
frequency of apoptosis.
The apoptotic response in the large intestinal epithelium was attenuated relative to that in the small intestine. The acute response (at 4 hours) was very similar. However, at the later time points, apoptotic events were much less frequent in the large bowel. This was associated with a greater percentage of cells within the large bowel crypts showing radiation-induced p21WAF-1/CIP1 expression and a lower frequency of p53-positive cells, especially those demonstrating strong immunoreactivity.
These data support the hypothesis that the fate of an individual cell
to undergo either p53-mediated growth arrest or apoptosis in response
to -radiation is dependent on the concentration of active p53
protein, with high p53 expression resulting in apoptosis and low p53
expression resulting in growth arrest. Similar proposals regarding p53
action have been put forward by others using in vitro
models.35-37
At levels of p53 expression below that
capable of inducing neither growth arrest nor apoptosis, p53 has been
proposed to suppress apoptosis36
and to promote
differentiation.37
Such a hypothesis suggests that
p53-binding domains, within promoter sequences of p53-regulated genes,
display different affinities for binding p53. It could be, therefore,
that the p53-binding domain of the p21WAF-1/CIP1
has a higher affinity for p53 than that of the p53-regulatory sequences
in genes that regulate the apoptotic process within the cell, as
originally suggested by Chen et al.35
This is certainly
true for mutant forms of p53.38,39
Studies by Gottlieb et
al40
suggest that p53 function may show cell- and
tissue-specific regulation in vivo.
What determines the degree of p53 expression within the different cell populations in the small intestinal crypts and the intestinal epithelium as a whole? Factors that could affect the degree of p53 protein expression include the ability of the cell to detect DNA damage and the efficiency of signal transduction pathways between DNA damage-recognition proteins and effector proteins such as p53. The failure of such pathways is clearly illustrated in individuals with ataxia telangiectasia.3 Transcriptional regulation of the p53 gene itself through signal transduction pathways may also be of some importance. Studies by Komarova et al41 suggest that the absolute level of p53 mRNA transcript within a cell directly determines the ability of the cell to up-regulate and maintain p53 protein levels. Finally, regulation may occur by the targeting of p53 protein for inactivation/degradation via the binding of mdm-2.42-45
Cell- and tissue-specific variation in the efficacy of p53 to execute either cell cycle arrest or apoptosis could be determined by the expression of other proteins that directly interact with p53 to affect its transcriptional activity. Examples of such proteins are IRF-146 and p33ING1,47 both of which have been shown to be essential for the transcriptional activity of p53 in vitro.
It has been demonstrated that there is an association between the
expression of p21WAF-1/CIP1 and attenuation of apoptosis.
Waldman et al48,49
have shown that after treatment with
agents such as Adriamycin and -radiation, the human colorectal tumor
cell line HCT116, which has transcriptionally functional p53, underwent
cell cycle arrest. However, cell clones with nonfunctional
p21WAF-1/CIP1 underwent apoptosis.48. Waldman
et al49
also demonstrated this effect of
p21WAF-1/CIP1 expression in vivo, using HCT116
xenografts in nude mice. Similar results using the same colorectal cell
line were obtained by Wouters et al.50
Studies by Polyak et
al51
and Chen et al35
suggest that enforced
expression of wt p53 in tumor cell lines can induce apoptosis
irrespective of p21WAF-1/CIP1 status. These studies
suggest, therefore, that p21WAF-1/CIP1 does not provide a
dominant signal for the suppression of apoptosis and fit well with
observations of cell- and tissue-dependent efficacy of p53-mediated
transcriptional activation.40
One of the major differences between the response of the large and
small intestinal epithelial cells to -radiation was the relative
longevity of p53 and p21WAF-1/CIP1 expression observed in
the large bowel. One possible reason is that cell proliferation within
the crypts of the large intestine is much slower compared with the
crypts of the small intestine (cell cycle times are 12 hours and 35
hours for crypt epithelium from murine small and large intestine,
respectively: also, the number of cells undergoing DNA synthesis at
anyone time is two to three times greater in the small
intestine).52
Therefore, labeled cells migrate more slowly
up the crypts in the large intestine. The large intestinal crypts are
also longer than those in the small intestine (large intestinal crypt
length is approximately 45 cells, compared with small intestinal crypt
length, which is approximately 25 cells). Immunoreactivity is,
therefore, observed for a longer period in the large intestinal crypt
epithelium.
In summary, -radiation exposure resulted in apoptosis and a
reduction in the fraction of proliferating cells, as indicated by a
decrease in [3H]thymidine incorporation. These cellular
responses were associated with a time- and dose-dependent increase in
the expression of p53 and p21WAF-1/CIP1. Heterogeneity in
the response of the small intestinal epithelium to -radiation was
observed. Cells at the base of the small intestinal crypts showed
strong p53 expression and a higher frequency of apoptosis relative to
the cells toward the top of the crypt. The latter showed primarily weak
p53 expression that was correlated with an increased frequency of
p21WAF-1/CIP1 expression and cell survival. Regional
variation was also noted in the response of the intestinal epithelium
to ionizing radiation. The small bowel showed a greater increase in
radiation-induced p53 expression, relative to the large bowel, with
greater numbers of p53 positive cells at all time points up to 48
hours. A larger proportion of cells that were strongly positive for p53
was also observed in the small bowel. In contrast, a greater number of
p21WAF-1/CIP1-positive cells were found in the large
intestinal epithelium and also in the top half of the small intestinal
crypts; this was associated with a lower frequency of radiation-induced
apoptosis in these regions. Coincidence between
p21WAF-1/CIP1 expression and resistance to
-radiation-induced apoptosis has been observed by
others.48-51
However, it has been shown that
p21WAF-1/CIP1 does not act as a dominant suppressor of
apoptosis.35,51
It would appear, therefore, that resistance
to -radiation-induced apoptosis is related to a reduced ability to
increase functional p53 to a level sufficient to initiate apoptosis.
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Footnotes |
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Supported by the Cancer Research Campaign. DMP is funded by the British Digestive Foundation and the Medical Research Council.
Accepted for publication May 30, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-irradiation. Oncogene 1997, 14:2759-2766[Medline]
-irradiation. Oncogene 1994, 9:1767-1773[Medline]
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