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PMC0
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10.1371%2Fjournal.pbio.1000324
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introduction
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Exposure to ionizing radiation (including γ or X rays) is strongly associated with cancer etiology in humans and mouse models [>>1<<],[2]. Since cancer development requires the accumulation of oncogenic mutations and mutagen exposure has been shown to cause cancer, predominant paradigms attribute the carcinogenic action of mutagenic carcinogens (including radiation) to
n3:mentions
n2:10688860
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_:vb7202572
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Exposure to ionizing radiation (including γ or X rays) is strongly associated with cancer etiology in humans and mouse models [1],[>>2<<]. Since cancer development requires the accumulation of oncogenic mutations and mutagen exposure has been shown to cause cancer, predominant paradigms attribute the carcinogenic action of mutagenic carcinogens (including radiation) to the
n3:mentions
n2:17336261
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_:vb7202573
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has been shown to cause cancer, predominant paradigms attribute the carcinogenic action of mutagenic carcinogens (including radiation) to the induction of genetic and epigenetic alterations in oncogenes and tumor suppressor genes [>>1<<],[3],[4]. On the other hand, various investigators have proposed that carcinogenic treatments increase the selective advantages conferred by certain oncogenic mutations, thereby initiating tumorigenesis [5]–[9].
n3:mentions
n2:10688860
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_:vb7202574
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has been shown to cause cancer, predominant paradigms attribute the carcinogenic action of mutagenic carcinogens (including radiation) to the induction of genetic and epigenetic alterations in oncogenes and tumor suppressor genes [1],[>>3<<],[4]. On the other hand, various investigators have proposed that carcinogenic treatments increase the selective advantages conferred by certain oncogenic mutations, thereby initiating tumorigenesis [5]–[9].
n3:mentions
n2:11900255
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_:vb7202575
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On the other hand, various investigators have proposed that carcinogenic treatments increase the selective advantages conferred by certain oncogenic mutations, thereby initiating tumorigenesis [>>5<<]–[9]. While ionizing irradiation is an archetypal mutagenic carcinogen, the causal link between induction of mutations in oncogenic loci and carcinogenesis is mostly inferential. On the other hand, ionizing irradiation clearly induces
n3:mentions
n2:15818400
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On the other hand, various investigators have proposed that carcinogenic treatments increase the selective advantages conferred by certain oncogenic mutations, thereby initiating tumorigenesis [5]–[>>9<<]. While ionizing irradiation is an archetypal mutagenic carcinogen, the causal link between induction of mutations in oncogenic loci and carcinogenesis is mostly inferential. On the other hand, ionizing irradiation clearly induces multiple
n3:mentions
n2:17109012
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_:vb7202577
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On the other hand, ionizing irradiation clearly induces multiple changes both within cells and in their microenvironment [>>1<<],[10]. Thus, the carcinogenic effect of irradiation might not be limited to causation of mutations in cancer-related genes but may also be attributed to increased selection for certain oncogenic events, which are either preexisting or
n3:mentions
n2:10688860
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_:vb7202578
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On the other hand, ionizing irradiation clearly induces multiple changes both within cells and in their microenvironment [1],[>>10<<]. Thus, the carcinogenic effect of irradiation might not be limited to causation of mutations in cancer-related genes but may also be attributed to increased selection for certain oncogenic events, which are either preexisting or
n3:mentions
n2:16327765
Subject Item
_:vb7202579
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P53 is a critically important tumor suppressor that mediates responses to a variety of cellular stresses and has well-characterized roles in mediating cell cycle arrest and apoptosis in response to genotoxic stress [>>11<<]. The p53 gene is mutated in about half of human tumors, and many tumors that retain wild-type (WT) p53 contain mutations that disrupt p53 regulation.
n3:mentions
n2:10065152
Subject Item
_:vb7202580
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A number of studies have documented that loss of p53 function confers a survival advantage following γ-irradiation in short-term survival assays [>>11<<]. In particular, p53 confers a dramatic protection of thymocytes from γ-irradiation induced apoptosis in vivo [12]–[14]. Ex vivo, p53 null hematopoietic cells are resistant to irradiation-induced death and to loss of clonogenic potential
n3:mentions
n2:10065152
Subject Item
_:vb7202581
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n3:Context
rdf:value
In particular, p53 confers a dramatic protection of thymocytes from γ-irradiation induced apoptosis in vivo [>>12<<]–[14]. Ex vivo, p53 null hematopoietic cells are resistant to irradiation-induced death and to loss of clonogenic potential [14]–[18]. On the other hand, short-term resistance to genotoxic stress conferred by p53 mutation often does not
n3:mentions
n2:8479522
Subject Item
_:vb7202582
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n3:Context
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In particular, p53 confers a dramatic protection of thymocytes from γ-irradiation induced apoptosis in vivo [12]–[>>14<<]. Ex vivo, p53 null hematopoietic cells are resistant to irradiation-induced death and to loss of clonogenic potential [14]–[18]. On the other hand, short-term resistance to genotoxic stress conferred by p53 mutation often does not
n3:mentions
n2:8516323
Subject Item
_:vb7202583
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n3:Context
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Ex vivo, p53 null hematopoietic cells are resistant to irradiation-induced death and to loss of clonogenic potential [>>14<<]–[18]. On the other hand, short-term resistance to genotoxic stress conferred by p53 mutation often does not correlate with long-term survival advantages [19], which might reflect the frequent incompatibility of extensive DNA damage with
n3:mentions
n2:8516323
Subject Item
_:vb7202584
rdf:type
n3:Context
rdf:value
Ex vivo, p53 null hematopoietic cells are resistant to irradiation-induced death and to loss of clonogenic potential [14]–[>>18<<]. On the other hand, short-term resistance to genotoxic stress conferred by p53 mutation often does not correlate with long-term survival advantages [19], which might reflect the frequent incompatibility of extensive DNA damage with
n3:mentions
n2:9865712
Subject Item
_:vb7202585
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n3:Context
rdf:value
On the other hand, short-term resistance to genotoxic stress conferred by p53 mutation often does not correlate with long-term survival advantages [>>19<<], which might reflect the frequent incompatibility of extensive DNA damage with long-term survival.
n3:mentions
n2:15738985
Subject Item
_:vb7202586
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Germline disruption of p53 in mice leads to lethal thymomas and sarcomas with 100% penetrance [>>20<<]–[22]. While γ-irradiation accelerates development of malignancies in newborn p53−/− mice, this acceleration is not seen in adult p53−/− mice [23].
n3:mentions
n2:8275085
Subject Item
_:vb7202587
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n3:Context
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Germline disruption of p53 in mice leads to lethal thymomas and sarcomas with 100% penetrance [20]–[>>22<<]. While γ-irradiation accelerates development of malignancies in newborn p53−/− mice, this acceleration is not seen in adult p53−/− mice [23].
n3:mentions
n2:1552940
Subject Item
_:vb7202588
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While γ-irradiation accelerates development of malignancies in newborn p53−/− mice, this acceleration is not seen in adult p53−/− mice [>>23<<]. However, irradiation dramatically accelerates tumorigenesis in p53 heterozygous (+/−) adult mice, and most of the resulting tumors exhibit loss of the second p53 allele [23], suggesting that loss of p53 function may be selected for
n3:mentions
n2:7987394
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_:vb7202589
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However, irradiation dramatically accelerates tumorigenesis in p53 heterozygous (+/−) adult mice, and most of the resulting tumors exhibit loss of the second p53 allele [>>23<<], suggesting that loss of p53 function may be selected for following irradiation.
n3:mentions
n2:7987394
Subject Item
_:vb7202590
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This latter possibility is supported by the observation that many oncogenic mutations that normally activate apoptotic or senescence responses can drive strong proliferation in cells with disrupted p53 function [>>24<<].
n3:mentions
n2:15549092
Subject Item
_:vb7202591
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n8:Section
dc:title
materials and methods
n8:contains
_:vb7202592 _:vb7202593 _:vb7202594 _:vb7202595
Subject Item
_:vb7202592
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MiG constructs expressing DDp53 (“dimerization domain” of p53) have been previously described [>>51<<]. Viral particles were assembled using ψNX-Eco packaging cells as previously described [51].
n3:mentions
n2:16277552
Subject Item
_:vb7202593
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n3:Context
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Viral particles were assembled using ψNX-Eco packaging cells as previously described [>>51<<]. Freshly isolated BM cells were transduced with retrovirus containing ψNX-Eco supernatants in non-adhesive six-well plates using the spin-fection technique (centrifugation at 910 g for 1.5 h in the presence of 8 μg/ml polybrene). Cells
n3:mentions
n2:16277552
Subject Item
_:vb7202594
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p53−/− mice [>>21<<] were purchased from Jackson Labs. GFP Tg mice were the generous gift of the Kappler/Marrack lab [29].
n3:mentions
n2:7922305
Subject Item
_:vb7202595
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n3:Context
rdf:value
GFP Tg mice were the generous gift of the Kappler/Marrack lab [>>29<<]. GFP Tg and p53−/− animals were backcrossed together into the Balb/c background for 10−11 generations.
n3:mentions
n2:12088410
Subject Item
_:vb7202596
rdf:type
n8:Section
dc:title
results
n8:contains
_:vb7202612 _:vb7202613 _:vb7202608 _:vb7202609 _:vb7202610 _:vb7202611 _:vb7202597 _:vb7202598 _:vb7202599 _:vb7202604 _:vb7202605 _:vb7202606 _:vb7202607 _:vb7202600 _:vb7202601 _:vb7202602 _:vb7202603
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DDp53 encodes for the multimerization domain of p53 (amino acids 302-390), and expression of DDp53 leads to potent inhibition of endogenous p53 activity [>>25<<],[26]. The transplanted animals were allowed to recover for 6 wk, at which point hematopoiesis was restored with relatively normal peripheral leukocyte counts (unpublished data). At this point, roughly 2% of the cells were GFP+ both in
n3:mentions
n2:8137820
Subject Item
_:vb7202598
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n3:Context
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DDp53 encodes for the multimerization domain of p53 (amino acids 302-390), and expression of DDp53 leads to potent inhibition of endogenous p53 activity [25],[>>26<<]. The transplanted animals were allowed to recover for 6 wk, at which point hematopoiesis was restored with relatively normal peripheral leukocyte counts (unpublished data). At this point, roughly 2% of the cells were GFP+ both in myeloid
n3:mentions
n2:17515610
Subject Item
_:vb7202599
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a context wherein the fate of a small percentage of p53 disrupted hematopoietic progenitors can be monitored in an otherwise WT background and that also eliminates potential effects of p53 deficiency in non-hematopoietic tissues [>>27<<],[28].
n3:mentions
n2:15753354
Subject Item
_:vb7202600
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a context wherein the fate of a small percentage of p53 disrupted hematopoietic progenitors can be monitored in an otherwise WT background and that also eliminates potential effects of p53 deficiency in non-hematopoietic tissues [27],[>>28<<].
n3:mentions
n2:16360031
Subject Item
_:vb7202601
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For these experiments, the null p53 allele [>>21<<] was bred into a transgenic (Tg) line that expresses GFP in all tissues from the Ubiquitin-C promoter [29].
n3:mentions
n2:7922305
Subject Item
_:vb7202602
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For these experiments, the null p53 allele [21] was bred into a transgenic (Tg) line that expresses GFP in all tissues from the Ubiquitin-C promoter [>>29<<]. We generated mosaic mice by transplantation of lethally irradiated recipients with WT BM mixed 7∶1 with either p53+/+ or p53−/− GFP Tg BM. After hematopoiesis was allowed to recover for 6 wk, the mice were sublethally irradiated (2.5 Gy)
n3:mentions
n2:12088410
Subject Item
_:vb7202603
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CD4+CD8+ (double-positive; DP) T cell progenitors in the thymus are known to be very sensitive to irradiation-induced apoptosis [>>12<<],[13]. Indeed, at 48 h post-irradiation we observed dramatic ablation of the DP population, while single-positive cells remained relatively unaffected (Figure S7).
n3:mentions
n2:8479522
Subject Item
_:vb7202604
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CD4+CD8+ (double-positive; DP) T cell progenitors in the thymus are known to be very sensitive to irradiation-induced apoptosis [12],[>>13<<]. Indeed, at 48 h post-irradiation we observed dramatic ablation of the DP population, while single-positive cells remained relatively unaffected (Figure S7).
n3:mentions
n2:8479523
Subject Item
_:vb7202605
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n3:Context
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We next examined the effect of irradiation on hematopoietic stem cells (HSC) by examining the HSC-enriched CD150+ Linneg/CD48neg BM compartment [>>30<<]. In contrast to the lymphoid progenitor pools, CD150+ Linneg/CD48neg cell numbers were not affected by irradiation, and we did not observe changes in the percentages of p53−/− cells (Figures S5B and S6E).
n3:mentions
n2:16219798
Subject Item
_:vb7202606
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Protection from immediate irradiation-induced ablation does not necessarily correlate with maintenance of long-term proliferative capacity [>>19<<]. Therefore, we assessed the impact of p53 disruption on maintenance of clonogenic capacity by progenitor and stem cells.
n3:mentions
n2:15738985
Subject Item
_:vb7202607
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for granulocytic/erythroid/megakaryocyte/macrophage progenitors or CFU-B for B-lymphoid progenitors) or transplanted into lethally irradiated mice for determination of CFU in spleens (CFU-S, derived from early multipotent progenitors) [>>31<<]. Consistent with the analyses above, irradiation resulted in dramatic reductions in CFU-GEMM, CFU-B, and CFU-S numbers (from 20× to 100×; Figure 4B), and p53 disruption provided substantial protection from irradiation-induced elimination
n3:mentions
n2:18371361
Subject Item
_:vb7202608
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n3:Context
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Since irradiation can dramatically reduce the competitive ability of HSC [>>32<<], we used competitor BM harvested from previously irradiated donors, in order to ensure that contributions of irradiated “test” HSC are not masked by non-irradiated competitors.
n3:mentions
n2:19738065
Subject Item
_:vb7202609
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have demonstrated that hematopoietic progenitors suffer from impaired functional capacity long after the acute effects of irradiation have been reversed; i.e., irradiation-induced loss of functional capacity appears to be permanent [>>32<<],[33]. We therefore asked whether p53 disruption protects hematopoietic progenitors from this long-term reduction of functional capacity.
n3:mentions
n2:19738065
Subject Item
_:vb7202610
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demonstrated that hematopoietic progenitors suffer from impaired functional capacity long after the acute effects of irradiation have been reversed; i.e., irradiation-induced loss of functional capacity appears to be permanent [32],[>>33<<]. We therefore asked whether p53 disruption protects hematopoietic progenitors from this long-term reduction of functional capacity.
n3:mentions
n2:16150936
Subject Item
_:vb7202611
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By 6 wk post-irradiation, BM cellularity and the numbers of early progenitors are restored [>>32<<], and thus these assays measure the impact of p53 disruption on stable reductions of fitness per progenitor caused by irradiation, as opposed to the immediate physical or functional elimination of hematopoietic progenitors.
n3:mentions
n2:19738065
Subject Item
_:vb7202612
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n3:Context
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selection for p53 deficiency is in part due to additional oncogenic events that are induced by irradiation and whose ability to drive uncontrolled proliferation is permitted by the lack of p53′s critical tumor suppressive function [>>24<<]. Should this be the case, then one would expect that once a cell has acquired the ability for uncontrolled proliferation, this clone will expand whether or not competing cells were irradiated.
n3:mentions
n2:15549092
Subject Item
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As the myeloid lineage is most responsive to changes in HSC pools [>>34<<], these data indicate that non-irradiated competitors can reverse selection for p53 disruption within irradiated early progenitor pools.
n3:mentions
n2:11729320
Subject Item
_:vb7202614
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n8:Section
dc:title
discussion
n8:contains
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The resistance of p53-deficient hematopoietic cells to irradiation-induced apoptosis was shown more than 10 years ago [>>12<<]–[16]. However, the relevance of this immediate protection towards long-term selective advantage in competitive contexts has not been directly demonstrated. Indeed, many cell types fail to show p53 dependence for long-term survival upon
n3:mentions
n2:8479522
Subject Item
_:vb7202616
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The resistance of p53-deficient hematopoietic cells to irradiation-induced apoptosis was shown more than 10 years ago [12]–[>>16<<]. However, the relevance of this immediate protection towards long-term selective advantage in competitive contexts has not been directly demonstrated. Indeed, many cell types fail to show p53 dependence for long-term survival upon
n3:mentions
n2:9003693
Subject Item
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Indeed, many cell types fail to show p53 dependence for long-term survival upon genotoxic stress despite a clear protection by p53 disruption in short-term assays [>>19<<],[36]. Our results demonstrate that in addition to providing a direct survival advantage, loss of p53 also protects hematopoietic progenitors from severe irradiation-induced loss of clonogenic capacity.
n3:mentions
n2:15738985
Subject Item
_:vb7202618
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Indeed, many cell types fail to show p53 dependence for long-term survival upon genotoxic stress despite a clear protection by p53 disruption in short-term assays [19],[>>36<<]. Our results demonstrate that in addition to providing a direct survival advantage, loss of p53 also protects hematopoietic progenitors from severe irradiation-induced loss of clonogenic capacity.
n3:mentions
n2:10197600
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This reduction is consistent with a recent report that irradiation induces hallmarks of senescence in an HSC-enriched population [>>33<<]. In addition to the reduction in numbers of functional stem and progenitor cells, irradiation appears to limit clonal potential per cell. Importantly, the loss of p53 function preserves both the numbers of functional stem/progenitor cells
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Homozygous p53−/− mice are highly prone to spontaneous T-cell lymphomas [>>20<<],[21]. While p53 heterozygous mice exhibit much later onset and penetrance of malignancies, they rapidly succumb to lymphomas following irradiation, and these lymphomas invariably lose the WT p53 allele [23].
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Homozygous p53−/− mice are highly prone to spontaneous T-cell lymphomas [20],[>>21<<]. While p53 heterozygous mice exhibit much later onset and penetrance of malignancies, they rapidly succumb to lymphomas following irradiation, and these lymphomas invariably lose the WT p53 allele [23].
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While p53 heterozygous mice exhibit much later onset and penetrance of malignancies, they rapidly succumb to lymphomas following irradiation, and these lymphomas invariably lose the WT p53 allele [>>23<<]. One possible explanation for the induction of p53 null lymphomas in p53 heterozygous mice is that irradiation selects for pre-existing or irradiation induced p53 loss-of-heterozygosity events, thereby increasing the target size for
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On the other hand, a more prevalent interpretation attributes the carcinogenic effect of irradiation to the induction of new oncogenic mutations [>>1<<]. Given the critical importance of p53 in arresting/killing cells with oncogenic mutations [24], many growth-promoting mutations would be expected to synergize with p53 loss in driving abnormal cell expansion and proliferation, in which
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Given the critical importance of p53 in arresting/killing cells with oncogenic mutations [>>24<<], many growth-promoting mutations would be expected to synergize with p53 loss in driving abnormal cell expansion and proliferation, in which case the selection for p53 mutation itself might be irrelevant.
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that the essential tumor suppressor function of p53 during irradiation-induced tumorigenesis is to eliminate cells with activated oncogenes, while the p53-dependent elimination of cells with radiation-induced DNA damage is dispensable [>>37<<]. Complementary experiments by Donehower and colleagues demonstrated that inactivation of p53 2 wk post-irradiation leads to promotion of lymphomas, virtually indistinguishable from promotion of lymphomas by disruption of p53 prior to
n3:mentions
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experiments by Donehower and colleagues demonstrated that inactivation of p53 2 wk post-irradiation leads to promotion of lymphomas, virtually indistinguishable from promotion of lymphomas by disruption of p53 prior to irradiation [>>38<<], supporting the conclusions reached by Evan and colleagues.
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Moreover, the expansion of p53 progenitor clones should further promote lymphoma development by augmenting genetic instability [>>11<<],[39]–[41], thus increasing the genetic diversity available to fuel malignant evolution (Figure 8C).
n3:mentions
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Moreover, the expansion of p53 progenitor clones should further promote lymphoma development by augmenting genetic instability [11],[>>39<<]–[41], thus increasing the genetic diversity available to fuel malignant evolution (Figure 8C).
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Moreover, the expansion of p53 progenitor clones should further promote lymphoma development by augmenting genetic instability [11],[39]–[>>41<<], thus increasing the genetic diversity available to fuel malignant evolution (Figure 8C).
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Still, irradiation does accelerate tumor development in p53−/− mice less than 7 d old (but not in adult p53−/− mice) [>>23<<], as well as in the mouse model used by the Donehower group [38].
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Still, irradiation does accelerate tumor development in p53−/− mice less than 7 d old (but not in adult p53−/− mice) [23], as well as in the mouse model used by the Donehower group [>>38<<]. Moreover, co-transplantation of unirradiated BM failed to prevent irradiation-promoted lymphomagenesis despite strongly inhibiting selection for p53 mutant cells (Figure 8A), although the inhibition of selection was substantially delayed
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Ultraviolet (UV) light exposure has been shown to increase the numbers and size of p53 mutant clones in human skin [>>42<<] and to induce the expansion of p53 mutant/Ras activated premalignant cells in organotypic skin cultures [43].
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Ultraviolet (UV) light exposure has been shown to increase the numbers and size of p53 mutant clones in human skin [42] and to induce the expansion of p53 mutant/Ras activated premalignant cells in organotypic skin cultures [>>43<<]. The expansion of p53 disrupted clones in mouse skin required continued UV-B exposure [44], contrasting with the stable selection for p53 disruption following a single exposure to X-irradiation in our studies.
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The expansion of p53 disrupted clones in mouse skin required continued UV-B exposure [>>44<<], contrasting with the stable selection for p53 disruption following a single exposure to X-irradiation in our studies.
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Of interest, conferring increased apoptosis resistance to skin cells actually hampers the expansion of p53−/− clones and the frequency of UV-induced skin cancers in mice [>>45<<]. Of course, selection for p53 loss is not limited to contexts of initiation. Within established tumors, chemotherapy leading to DNA damage and anti-angiogenic therapy leading to hypoxia have each been shown to potently select for p53
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Within established tumors, chemotherapy leading to DNA damage and anti-angiogenic therapy leading to hypoxia have each been shown to potently select for p53 disruption [>>24<<],[46],[47].
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Within established tumors, chemotherapy leading to DNA damage and anti-angiogenic therapy leading to hypoxia have each been shown to potently select for p53 disruption [24],[>>46<<],[47].
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Within established tumors, chemotherapy leading to DNA damage and anti-angiogenic therapy leading to hypoxia have each been shown to potently select for p53 disruption [24],[46],[>>47<<].
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For example, the skin cancer-associated mutational spectra in INK4A and p53 genes are specific to UV light-induced mutagenesis [>>48<<]–[50]. On the other hand, the presence of an initiating mutation is not sufficient for tumorigenesis unless the mutation leads to clonal expansion, as the small target size of an unselected mutant clone should substantially limit the
n3:mentions
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For example, the skin cancer-associated mutational spectra in INK4A and p53 genes are specific to UV light-induced mutagenesis [48]–[>>50<<]. On the other hand, the presence of an initiating mutation is not sufficient for tumorigenesis unless the mutation leads to clonal expansion, as the small target size of an unselected mutant clone should substantially limit the chances
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Notably, genetic alterations unique to ionizing radiation are not evident in cancers associated with radiation exposure [>>1<<].
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in the context of previous irradiation p53 inhibition failed to provide a stable selective advantage (Figure 6), cells that expressed the Notch1 mutant ICN were strongly selected for within previously irradiated progenitor cell pools [>>32<<]. Notably, co-transplantation of non-irradiated hematopoiesis potently inhibits both selection for ICN expressing cells and the resulting leukemogenesis.
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The ability of healthy WT competitors to limit expansion of oncogenically mutated cells has also been demonstrated in other contexts of genetic or chemical impairment of cell proliferation [>>51<<],[52]. Thus, the expansion of an initiated clone requires both conditions of reduced fitness within a progenitor pool and the presence of cells with oncogenic mutations adaptive or resistant to the particular fitness-reducing context.
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The ability of healthy WT competitors to limit expansion of oncogenically mutated cells has also been demonstrated in other contexts of genetic or chemical impairment of cell proliferation [51],[>>52<<]. Thus, the expansion of an initiated clone requires both conditions of reduced fitness within a progenitor pool and the presence of cells with oncogenic mutations adaptive or resistant to the particular fitness-reducing context.
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