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Molecular Biology and Genetics |
Department of Immunology and Oncology, National Center of Biotechnology (Spanish Council for Scientific Research), Campus de Cantoblanco, Madrid E-28049 [J. M-C., M. S.], and Department of Animal Pathology II, Veterinary School, Universidad Complutense de Madrid, Madrid E-28040 [J. M. F., P. G-P.], Spain
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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65% of the tumors), endothelial (20%), and epithelial (10%) tumors. We have also studied radiation-induced carcinogenesis to test whether, in this setting, p53 exerts its tumor suppressor activity mainly through apoptosis, rather than through p21-mediated cell-cycle arrest. Concurring with this, p21-deficient mice did not show increased susceptibility to radiation-induced carcinogenesis. On the contrary, they were protected relative to wild-type mice. We conclude that p21, by mediating p53-dependent cell-cycle arrest, plays a significant role in tumor suppression. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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p53 is a convergence point for various types of cellular stresses, notably DNA damage and oncogenic stress (20, 21, 22) . Both types of stress are conveyed to p53 through separate routes. DNA damage is signaled by the related kinases ATM and ATR (20) , whereas oncogenic stress is signaled by the tumor suppressor p19ARF (21) . p53 activation by any of these routes results in up-regulation of a large set of p53-transcriptional targets, many of which have been identified recently (23 , 24) using DNA microarrays. Among the multiple p53 transcriptional targets, p21 stands out as the main, although not exclusive, effector of p53-mediated cell cycle arrest (8, 9, 10) . Other p53 targets contribute to apoptosis induction, such as Bax, Noxa, and p53AIP1 (20 , 22) , or to the maintenance of genomic stability, such as GADD45a (25) .
Inactivating mutations in either p53 or in some of its upstream regulators, notably ATM and p19ARF, are common in human cancers. In contrast, mutations in the various p53-transcriptional targets studied so far, including p21, are uncommon (26) . However, it remains to be elucidated which is the relative contribution of the different p53-transcriptional targets to tumor suppression. Regarding p21-null mice, it was originally reported (9) that they are tumor-free at least until 7 months of age. Subsequently, the role of p21 in mediating tumor suppression has been examined in a number of murine models for tissue-specific tumorigenesis. The absence of p21 accelerates the development of some tumors, particularly pituitary tumors in Rb-haploinsufficient mice and in p18INK4c-deficient mice (27 , 28) , breast tumors in mouse mammary tumor virus/ras transgenic mice (29) , and intestinal tumors in Apc-haploinsufficient mice (30) . In contrast, the absence of p21 has no effect on the tumor-prone phenotype of mice lacking the Werner syndrome gene (31) , and, more surprisingly, it even delays the onset of thymic lymphomas in ATM-null mice (32) . Finally, there are contradictory results concerning the susceptibility of p21-null mice to chemically induced carcinogenesis of the skin (33 , 34) . In this study, we have addressed the role of p21 in tumor suppression by directly assessing the susceptibility of p21-null mice to spontaneous tumors and also to radiation-induced tumors.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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-radiation tumorigenesis, 1-month-old mice were irradiated weekly for 4 weeks with a 1.75-Gy dose from a 137Cs source (MARK 1-30 Irradiator; Shepherd & Associates) at a rate of 1.14 Gy/min.
Histological Analysis.
Tumors from nonautolyzed tissues were recovered from moribund or recently deceased mice. Tissue samples were fixed in 10% buffered formalin, embedded in paraffin wax, sectioned at 4 µm, and stained with H&E. Immunohistochemical staining was performed using the streptavidin-biotin-peroxidase complex method. Tissue sections were processed with 10 mM citrate buffer (pH 6.0) in a microwave (100°C; 15 min), although in some cases 10-min pre-trypsinization was also required. Endogenous peroxidase activity was inactivated by incubation with 3% hydrogen peroxide in methanol (15 min; room temperature).
A battery of immunochemical markers was used to confirm tumor histogenesis. Hematopoietic malignancies were diagnosed using the following markers: for B- and T-lymphocyte detection, rat antimouse CD45R/B220 mAb (Southern Biotechnology Associates, Birmingham, AL; dilution 1:100); for T-lymphocyte detection, rabbit antihuman CD3 polyclonal antibody (Dako, Glostrup, Denmark; 1:100); and for monocyte/macrophage detection, rat antimouse F4/80 mAb (BMA Biomedicals AG, Augst, Switzerland; 1:20) and rat antimouse CD11b mAb (Chemicon International, Temecula, CA; 1:20). Mesenchymal tumors were diagnosed using goat antihuman vimentin polyclonal antibody (Sigma Chemical Co., St. Louis, MO; 1:40), rabbit antichicken desmin polyclonal antibody (Sigma Chemical Co.; 1:100), and rabbit antihuman factor VIII polyclonal antibody (Dako; 1:200). All of the antibodies were diluted in TBS. Primary antibodies were omitted for negative controls. Tissue sections were incubated in a humidity chamber (overnight; 4°C). After three rinses in TBS, 5 min each, samples were incubated with a secondary antibody. For detection of primary rabbit antibodies, we used biotinylated goat antirabbit IgG (Vector Laboratories, Burlingame, CA; 1:400). For primary rat antibodies, we used biotinylated rabbit antirat IgG (Vector Laboratories), and for primary mouse antibodies, we used biotinylated rabbit antimouse IgG (Vector Laboratories; 1:400). After 30-min incubation with the secondary antibody, tissue sections were incubated with streptavidin conjugated with peroxidase, diluted 1:20 in TBS (Zymed Laboratories, Inc.) for 30 min at room temperature. The chromogen was 3–3'-diaminobenzidine tetrahydrochloride (Sigma Chemical Co.), diluted 0.002% in TBS, in the presence of 0.01% hydrogen peroxide. Nuclei were counterstained with Harris hematoxylin for 1 min.
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RESULTS AND DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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. In comparison, only 26% of males died of glomerulonephritis at an average age of 13.2 months (Table 1)
. The elevated incidence of glomerulonephritis in p21-deficient mice, with increased severity among females, has been reported previously (35)
and is attributable to an autoimmune process produced by abnormal proliferation of memory T-cell lymphocytes.
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). The higher incidence of tumors among p21-null males, however, reflects the lower susceptibility to death by renal failure, and it is not indicative of a male-specific tumor susceptibility. For those p21-deficient mice (both males and females) that developed tumors, the average life span was 16 months (Table 1)
. The latency for spontaneous tumor development in p21-null mice is longer than in p53-null mice (5 months; Refs. 36, 37, 38
), and it is also longer than the latency in knockout mice for ATM (3 months; Refs. 39, 40, 41
) or p19ARF (10 months; Refs. 42
, 43
). In contrast, the proapoptotic protein and p53-transcriptional target, Bax, does not contribute to spontaneous tumor suppression, as deduced from the lack of tumors in Bax-deficient mice after a 2-year observation period (44)
. We conclude that p21 plays a significant role in tumor suppression, which is more important than that of Bax but weaker than that of p53 or its upstream regulators ATM and p19ARF.
Tumor Spectrum in p21-null Mice.
We have carried out a detailed histopathological analysis of all of the tumors spontaneously developed by p21-null mice (n = 65; Table 2
). Approximately half of the spontaneous tumors were histiocytic sarcomas (52% of the tumors; Table 2
). These tumors were characterized by the presence of macrophages infiltrating the affected organs. Macrophages were identified by their typical morphology, as well as by their reactivity to the cell surface marker F4/80 (Fig. 2A)
. The most commonly colonized organs were spleen and liver, and occasionally lymph nodes, bone marrow, and uterus. In the spleen, tumor cells grew in the red pulp, forming packed nodular groups of histiocytes. In the liver, tumor cells occupied the sinusoids and surrounded the central vein with a granulomatous pattern, often eroding the walls and invading the lumen (Fig. 2A)
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). These were mainly hemangiomas characterized by abundant capillaries lined by a single layer of well-differentiated endothelial cells. A small proportion of vascular tumors were hemangiosarcomas (Fig. 2B)
. These malignant tumors were formed by poorly delineated vascular channels lined by pleomorphic endothelial cells forming solid areas and with frequent mitotic figures. Endothelial cells were further identified by their reactivity to vimentin and factor VIII (see Fig. 2B
, inset). Both types of vascular tumors, hemangiomas and hemangiosarcomas, preferentially developed in the liver or the spleen.
Approximately 14% of all of the tumors were lymphomas affecting the lymph nodes and/or spleen, usually with small metastatic foci in liver, lungs, or kidneys (Table 2)
. All of the lymphomas involved the B-cell lineage and were further classified in most cases as centroblastic-centrocytic or centroblastic follicular B-cell lymphomas (Fig. 2C)
.
The p21-null mice also developed epithelial tumors (Table 2)
. In particular, we observed three lung carcinomas (Fig. 2D)
, two benign skin tumors (Fig. 2E)
, one Leydig cell adenoma of the testis, and one malignant Leydig cell tumor with lung metastatic nodules (Fig. 2F)
. Overall, about 10% of tumors were of epithelial origin (Table 2)
.
In conclusion, p21 deficiency results in the spontaneous development of a variety of tumors of hematopoietic, endothelial, and epithelial origin. This phenotype is reminiscent of the rich spectrum of spontaneous tumors developed by p53-null and by p19ARF-null mice (36, 37, 38 , 42 , 43) , albeit with a longer latency. It is interesting to note that p21-deficient mice did not develop T-cell lymphomas, which is one of the most common tumor types in p53-null and p19ARF-null mice (36, 37, 38 , 42 , 43) . Also, mice deficient in the p53-activating kinase ATM develop exclusively spontaneous T-cell lymphomas (39, 40, 41) .
Radiation-induced Carcinogenesis in p21-null Mice.
Ionizing radiation is a well-known tumorigenic agent, which preferentially induces thymic lymphomas in mice. The tumor suppressor p53 is critical in the protection of cells against radiation-induced carcinogenesis, most likely through its ability to trigger apoptosis of radiation-damaged cells (45)
. This is particularly evident in the case of the thymus, which undergoes massive p53-dependent apoptosis after radiation (46
, 47)
. p21 is highly induced by radiation in the thymus in a p53-dependent manner (48)
, but it is not required for thymocyte apoptosis (9)
. On the basis of this, we have hypothesized that p21-deficient mice should not have an increased susceptibility to radiation-induced tumorigenesis. We have evaluated the susceptibility of p21-deficient mice to -radiation carcinogenesis. As a control, irradiation of wild-type mice resulted in 100% mortality after a period of 9 months after irradiation, when the mice were 11 months old (Fig. 3
shows the survival curve of the females alone for the purpose of simplifying the discussion below); and mortality was mainly attributable to the development of T-cell lymphomas (Table 3)
. In contrast, irradiated p21-deficient mice survived longer than irradiated wild-type mice, and only one-third (32%) of them developed tumors (Table 3
; Fig. 3
). As it was the case among irradiated wild-type mice, the predominant tumors induced by radiation in p21-null mice were T-cell lymphomas (Table 3)
. These results clearly indicate that p21 deficiency does not increase the susceptibility to radiation-induced carcinogenesis, but, on the contrary, it provides a certain degree of protection delaying the appearance of thymic lymphomas. This protective effect could be attributable to an enhanced apoptotic response of the p21-null cells. Indeed, other investigators have reported previously (32)
that the radiation-toxicity syndrome is more severe in p21-deficient mice than in wild-type mice, and it is associated to an enhanced apoptotic response of the intestine in p21-null mice. We have considered the possibility that radiation could directly result in more apoptosis in the thymus of p21-null mice; however, quantitation of sub-(G0/G1) thymocytes after acute irradiation (10 Gy; and analysis 3 h after irradiation) has not supported this idea (data not shown). We have also examined the constitutive levels of apoptosis in the thymic lymphomas developed in p21-null mice and in wild-type mice after irradiation (Fig. 4)
. Interestingly, p21-null lymphomas exhibited a high level of apoptosis with tangible apoptotic bodies, often surrounded by a narrow halo indicative of phagocytosis (Fig. 4B)
. In contrast, lymphomas from wild-type mice had a uniform morphology with scarce evidence of apoptosis (Fig. 4A)
. We conclude that thymic lymphomas in p21-null mice have a significantly higher level of apoptosis compared with that in wild-type mice. Similar conclusions have been reached by other investigators (32)
after comparing the levels of constitutive apoptosis in thymic lymphomas of ATM-deficient mice versus ATM/p21-deficient mice. Also, lymphocytes in the spleen of p21-deficient mice have a high level of constitutive apoptosis in comparison with wild-type mice (49)
. All together, it appears that the absence of p21 entails a higher degree of apoptosis and, consequently, a growth disadvantage that can explain the delayed incidence of radiation-induced thymic lymphomas in p21-deficient mice.
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. This can be attributed to the complete absence of deaths by autoimmunity-related glomerulonephritis among the irradiated p21-null mice, both males and females (Table 3)
. This phenomenon is in agreement with the well-established observation that radiation, by eliminating autoreactive memory lymphocytes, delays the progression of autoimmune processes (50
, 51)
.
Concluding Remarks.
In this study, we have performed a detailed analysis of the survival and tumor susceptibility of p21-deficient mice. Our observations demonstrate that p21 contributes to tumor suppression, albeit to a lesser extent than p53. Notably, p21-null mice develop a variety of neoplasias, which include tumors of hematological, endothelial, and epithelial origin. Interestingly, p21-deficient mice did not develop T-cell lymphomas, which is one of the most common tumor types in p53-null mice (36, 37, 38)
. The development of spontaneous tumors in p21-null mice is in contrast to Bax-deficient mice, which do not develop tumors even after 2 years of age (44)
. We also show that in the specific case of radiation-induced carcinogenesis, p21 deficiency does not accelerate tumor development. On the contrary, p21 deficiency delays the onset of radiation-induced T-cell lymphomas, which is in line with the delay in the appearance of spontaneous T-cell lymphomas produced by p21 deficiency in ATM-null mice (32)
. It can be proposed that p21 contributes to mediate p53-dependent tumor suppression in some tumor types, which would include histiocytic sarcomas, hemangiomas, B-cell lymphomas, and lung carcinomas, but not in other tumor types, particularly spontaneous or radiation-induced T-cell lymphomas.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by grants from the Human Frontier Science Program, the Spanish Ministry of Science and Technology, the Regional Government of Madrid, and a core grant to the Department of Immunology and Oncology from the partnership between the Spanish Council for Scientific Research and The Pharmacia Corporation. 
2 To whom requests for reprints should be addressed, at National Center of Biotechnology, Campus de Cantoblanco, Madrid E-28049, Spain. Phone: 34-91-5854702; Fax: 34-91-3720493; E-mail: mserrano{at}cnb.uam.es
3 The abbreviations used are: CDK, cyclin-dependent kinase; mAb, monoclonal antibody; TBS, Tris-buffered saline.
Received 4/13/01. Accepted 6/19/01.
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