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Tumor Biology |
Howard Hughes Medical Institute [T. K., C. J. S.] and Departments of Tumor Cell Biology [T. K., E. V. d. K., D. H. R., C. J. S.] and Pathology [S. B.], St. Jude Children’s Research Hospital, and Department of Biochemistry (D. H. R.), University of Tennessee College of Medicine, Memphis, Tennessee 38105
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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As part of an earlier report that pinpointed ARF’s role as a tumor suppressor and described its dependence on p53, it was demonstrated that about one-third of a relatively small group of animals lacking ARF function died from spontaneous tumor development within the first 6 months of life (8) . We have now extended these studies using larger cohorts of animals, enabling us to more rigorously compare ARF-null animals with previously derived p53-null mice. Despite the dependence of p19ARF on p53, the spectrum of tumors arising in ARF-null animals differs in several key respects from the patterns that are characteristic of animals lacking p53 function.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Histological Analyses.
Tumors from nonautolyzed tissues recovered from moribund or recently deceased animals were histologically examined in detail. Bouin’s fixed or formalin-fixed paraffin-embedded tissues were analyzed by light microscopy and immunohistochemistry. Lymphomas were classified according to the criteria of Pattengale and Firth (14)
. Antigen retrieval of tissue sections was performed by microwaving in citrate buffer prior to immunostaining on a Ventana Nexus Automatic Immunostainer (Tucson, AZ). Primary antibodies, used according to the manufacturer’s recommendations, included: rabbit antiserum to human CD3 (A0452), which is cross-reactive to the cognate mouse protein; rabbit antibodies to murine glial fibrillary acidic protein (Z0334; both from Dako, Carpinteria, CA); and rat antibody to mouse CD45R/B220 (01121D, Pharmingen, San Diego, CA). Primary antibodies were incubated with sections for up to 1 h at 41°C. Biotinylated goat antirabbit secondary antibody, an avidin-biotin amplification system, and peroxidase staining reagents were all obtained from Vector Laboratories (Burlingame, CA).
Protein and RNA Expression.
Proteins were extracted from tumor tissues in ice-cold EBC buffer [50 mM Tris-HCl (pH 8.0) containing 120 mM NaCl, 0.5% NP40, and 1 mM EDTA], and immunoprecipitation and immunoblotting analyses were performed for p16INK4a and p15INK4b, as described previously (12)
; p19ARF was detected by direct immunoblotting as described in detail elsewhere (15)
. Total RNA, extracted from dissected tumor tissues, was used as a template for DNA synthesis, followed by PCR amplification and detection of products using ARF-specific exon 1ß primers and radiolabeled probe (5)
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RESULTS AND DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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; 19 of 24 such mice that could be analyzed exhibited spontaneously arising tumors of different histological types (included in Table 1
), whereas the other five died of unknown causes. As reported previously, tumor tissues from these animals continued to express the wild-type p16INK4a protein (8)
. Cancer development in untreated wild-type littermates housed as controls was not observed (0 of 45 animals), although a few of these mice also expired from unknown causes (Fig. 1A)
.
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. A smaller group of heterozygous mice followed for a longer time developed various forms of malignancy in their second year of life (Table 1)
. Analysis of two lymphomas and one squamous cell carcinoma from this cohort by use of PCR performed with ARF-specific exon 1ß primers indicated that the levels of ARF mRNA expression were significantly underrepresented as compared to normal tissues from the same animal (data not shown). In two other tumors, including a mammary carcinoma and a fibrosarcoma, in which genomic DNA was analyzed by Southern blotting, the blot signals arising from the functional ARF alleles were either underrepresented (Fig. 2A
, Lane 2) or absent (Fig. 2A
, Lane 4); we attribute the residual signal in Lane 2 to normal cells present within the excised mammary tissue. Importantly, p16INK4a and p15INK4b continued to be expressed in these tumor cells (Fig. 2B)
, indicating that INK4 sequences were retained (8)
. Together, these data indicated that the tumor cells, which made up the bulk of these analyzed samples, lacked ARF function. Moreover, although selection for ARF loss can involve codeletion of flanking INK4a and INK4b alleles from the wild-type chromosome, there was apparently no selective pressure for elimination of the wild-type INK4 alleles flanking the disrupted ARF locus on the other chromosome.
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) or ionizing radiation (Fig. 1C)
. This has also been observed in animals disrupted in exons 2 and 3 of the INK4a/ARF locus (7)
. In agreement with historical data with C57BL/6 mice (17
, 18) , DMBA primarily elicited epidermal tumors of skin in both wild-type (data not shown) and ARF-null animals, although the spectrum of tumor types was broadened in animals that lacked ARF function (see below).
Explanted cells or whole tissues taken from ARF-null animals manifest an intact p53-dependent checkpoint in response to 
-irradiation (8)
. Their responses to a 50% lethal dose of ionizing radiation are similar to those of wild-type littermates (19)
but differ significantly from p53-null mice, which tolerate the same X-ray dose (20)
. In a small group of animals treated neonatally with ionizing radiation, we observed a significant increase in the rapidity of tumor development (Fig. 1C)
, although in this series, the predominant tumors were lymphomas and sarcomas. Hence, DNA damage induced by ionizing radiation or chemical carcinogens appears to target as yet unidentified genes, the altered functions of which collaborate with ARF loss in tumor formation.
Spectrum of Tumor Types in ARF-null Animals.
We analyzed tumors in 19 animals housed for more than 1 year (Fig. 1A)
and in 16 additional mice maintained for a shorter period. The most common tumors arising spontaneously in ARF-null animals were sarcomas (43%; Tables 1
and 2
). Morphologically, the vast majority of these looked like typical fibrosarcomas, appearing as invasive, anaplastic spindle cell tumors without evidence of vascular, osseous, or nerve sheath differentiation (Fig. 3A)
. Because we did not formally exclude that the poorly differentiated spindle cell tumors in this group might have arisen from other mesenchymal cell types, they are classified generically in Tables 1
and 2
as sarcomas without further specification. In some cases, however, it was evident that these tumors had a more definitive origin. A malignant osteogenic sarcoma with frank pulmonary metastasis was observed in one animal from this group, and an angiogenic sarcoma metastatic to liver was seen in another.
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. Many of these tumors were morphologically lymphoblastic, stained positively with T-cell markers (e.g., CD3, shown in Fig. 3B
) and remained pseudodiploid when analyzed for DNA content by flow cytometry. Their phenotype mimics human pediatric T-cell lymphomas and leukemias, which frequently sustain INK4a/ARF deletions (21)
and retain a 2 N DNA content, unlike the more common pediatric tumors that arise from the B-cell lineage and are hyperploid (22)
. The single thymoma arising in this group was comprised predominantly of immature T cells, immunophenotyped without culture in vitro as CD3-positive, CD4-low, and CD8-negative cells. However, direct histological examination also revealed a substantial keratin-positive epithelial component in the tumor mass, leaving open the possibility that it represented a mixed tumor consisting of both lymphoid and carcinomatous components.
Intriguingly, the remaining ARF-null animals developed tumors that are rarely observed in either normal mice or in untreated p53-null animals. Three untreated animals but not any of those exposed to DMBA or X rays (see below) developed well-differentiated gliomas within 12–15 weeks of birth (Table 1)
that diffusely infiltrated the cerebral parenchyma (Fig. 3C)
. Spontaneously arising gliomas have not so far been observed in mice disrupted in exons 2 and 3 of the INK4a/ARF locus, which do not express either p16INK4a or p19ARF (7)
. However, the incidence of malignant glioblastomas rises markedly in INK4a/ARF-null cells engineered to overexpress a constitutively active epidermal growth factor receptor in glial precursor cells (23)
. INK4a/ARF loss and activating epidermal growth factor receptor mutations likely collaborate in gliomagenesis in humans as well (23, 24, 25, 26, 27, 28, 29)
. In both humans and mouse models, that subset of gliomas lacking INK4a/ARF remains pseudodiploid, whereas a second group of gliomas that, instead, manifests amplification of the cyclin-dependent kinase 4 gene (CDK4) and p53 loss tends to be hyperploid (30)
. Together, these data suggest that different mutations affecting the p53 and Rb pathways are likely to collaborate in the evolution of these central nervous system tumors.
Six ARF-null animals developed carcinomas (Tables 1
and 2
). These included two well-differentiated squamous cell tumors of the skin and two pulmonary adenocarcinomas (one of which is shown in Fig. 3F
). One mouse exhibited a poorly differentiated abdominal tumor, most suggestive of a highly malignant pancreatic carcinoma. Another animal had a salivary gland carcinoma that arose 8 weeks after birth and was the earliest tumor to appear in our series. As noted above, we could not exclude the presence of carcinomatous changes in the single thymic tumor listed in Table 2
as a lymphoid malignancy. A malignant nerve sheath tumor arising from cells surrounding nerves exiting the spinal cord was observed in a single untreated animal and in another heterozygous animal treated with DMBA (Fig. 3D
, Table 2
). One untreated animal (not listed in Table 1
) exhibited hyperplastic bone marrow consistent with an ill-defined myeloproliferative process. INK4a/ARF-null and pure ARF-null mice commonly manifest increased extramedullary hematopoiesis, sometimes accompanied by gross splenic enlargement (7
, 8)
, but the nature of the underlying disorder remains unresolved, and at least so far, frank leukemias have not been observed to arise later in the life of these animals.
Like untreated animals, irradiated ARF-null animals also manifested sarcomas (four of six) and lymphoma (one of six), suggesting that X-ray exposure shortened tumor latency without obviously affecting the frequency of tumor types (Fig. 1C
, Table 2
). One animal from this group exhibited a meningioma (Fig. 3E)
. In contrast, 10 of 13 animals treated with DMBA developed squamous cell carcinomas of the skin with various degrees of anaplasia and invasiveness (Fig. 1B
, Table 2
). In this group, the appearance of multiple tumor types at the time of diagnosis was relatively common. Two animals exhibited three entirely distinct tumors at autopsy, including squamous cell carcinoma, metastatic sarcoma, and a malignant adnexal tumor in one case and squamous carcinoma, sarcoma, and lymphoma in a second. In addition to their skin cancers, two other mice from this group developed either lymphoma or sarcoma. Three DMBA-treated animals without squamous cell carcinomas developed sarcomas, accompanied by a malignant adnexal tumor in one of these animals. Hence, DMBA targeted tumor development to skin, but it also accelerated the appearance of other tumor types. Despite the fact that tumorigenesis occurred with significant latency and likely requires several collaborating events (see above), the presence of multiple tumor types in individual DMBA-treated animals underscores the strong predisposing influence of ARF loss in tumor development.
Tumors Arising in ARF Heterozygotes.
Interestingly, only two sarcomas were observed among 12 untreated heterozygous animals that spontaneously developed tumors later in life (Table 1)
. Three animals exhibited angiomatous tumors arising in different organs, which were rarely observed in homozygous ARF-null animals (Table 2)
. Three lymphomas were also recorded in heterozygotes, but unlike the tumors in ARF-null mice, two lymphomas that appeared relatively late in life (Table 1)
expressed B-cell rather than T-cell markers. Three animals developed carcinomas of different types (breast, lung, and skin). The remaining animal exhibited myelofibrosis with marrow replacement.
Clearly, not only the latency but also the spectrum of tumors arising in ARF heterozygotes differs from the pattern observed in ARF-null mice, in that the frequency of sarcomas was lower, whereas carcinomas and angiomatous tumors appeared to be more common. This suggests that target tissues other than mesenchymal and lymphoid precursors may be at greater risk of sustaining loss of the second ARF allele as these animals age. Although our findings are generally compatible with the idea that ARF functions as a classical "two-hit" tumor suppressor (31) , we cannot formally exclude that ARF haploinsufficiency might also contribute.
ARF heterozygotes also responded to DMBA; developing tumors responded somewhat more rapidly than their wild-type littermates (Fig. 1B
, Table 2
). These tumors were moderately to well-differentiated papillary skin carcinomas, although one animal developed a nerve sheath tumor (see Fig. 3D
and the section above), and another developed pulmonary adenocarcinoma, as also seen in one of the untreated animals (Fig. 3F)
. Of four irradiated heterozygotes, two developed sarcoma and one lymphoma, whereas another animal developed mammary carcinoma (also seen in an untreated heterozygote). Deletion of the residual ARF allele in the mammary tumor cells of the irradiated animal (Fig. 2)
strongly argues that loss of ARF function contributed to carcinogenesis in this case.
ARF Loss versus p53 Loss in Tumorigenesis.
By interacting with the p53-negative regulator Mdm2, p19ARF stabilizes p53 and facilitates p53-dependent transcription, leading either to cell cycle arrest or apoptosis, depending on the biological setting. Recent data suggest several mechanisms by which p19ARF can nullify Mdm2 function. (a) p19ARF is a nucleolar protein, the overexpression of which can mobilize Mdm2 to the nucleolus; in turn, this may enable p53 to be stabilized in the nucleoplasm and help enforce its transcriptional activity (32)
. 4
(b) Mdm2 appears to act as an E3 ubiquitin ligase that triggers p53 degradation, and p19ARF can interfere with this function in vitro (33)
. Moreover, Mdm2 contains a nuclear export signal that targets Mdm2-p53 complexes for degradation in cytoplasmic proteasomes (34)
, so p19ARF binding to Mdm2 might abrogate its activity as a transporter. Hence, overexpression of p19ARF induces p53 activity, whereas cells lacking p53 are resistant to ARF’s effects.
Because ARF acts upstream of p53, a logical assumption is that mice lacking ARF would reveal defects similar to those observed in p53-null mice, and this is true in the sense that animals lacking either gene can develop normally but are highly tumor prone. However, ARF responds to a much narrower range of stress signals than p53, which is also induced by irradiation, hypoxia, and other DNA-damaging agents, such as cytotoxic drugs, none of which require ARF function to induce p53 (reviewed in Ref. 6
). In turn, the loss of p53 leads to significantly more rapid tumor development with a mean latency of 18–20 weeks (versus 38 weeks for ARF-null mice) and is accompanied by the spontaneous appearance of multiple tumor types in a small but significant subset of untreated animals (35
, 36)
. The vast majority of tumors in p53-null animals are lymphomas (71–77% in two independent series), with sarcomas representing most of the remainder and carcinomas being rare (35, 36, 37)
. This is consistent with the idea that p53 is important during lymphoid development, triggering apoptosis in lymphoid progenitors that have unrepaired DNA damage during ontogeny or expansion (38)
, although VDJ recombination per se is not likely to be the trigger (39
, 40)
. On the other hand, p53 heterozygotes develop tumors after a much longer latency, generally associated with the loss of the residual p53 allele; in this situation, sarcomas (57% incidence) predominate over lymphomas (25% incidence; Ref. 36
). Because thymic involution occurs early in life, the retarded loss of p53 function in heterozygotes would be expected to slow the rate of thymic lymphomagenesis, thereby allowing the emergence of other tumor types. By analogy, sarcomas become the most predominant in ARF-null mice, and possibly because these animals live significantly longer than their p53-null counterparts (up to 
15 months versus 6 months), tumors of the nervous system and carcinomas also become manifest. Spontaneous development of neural tumors and of most types of carcinoma are rare in normal mice, so we also suspect that ARF function is critical in countering tumorigenesis in these lineages as the animals age. This is consistent with observations in humans, in whom loss of the INK4a/ARF locus occurs in central nervous system tumors and in a wide variety of carcinomas (reviewed in Ref. 2
).
Tumor Spectrum in ARF-null versus INK4a/ARF-null Animals.
In many respects, the results described here are similar to the findings made earlier with animals lacking exons 2 and 3 of the INK4a/ARF locus (7)
. Because tumors in the ARF-null animals continue to express p16INK4a (Ref. 8
; also Fig. 2
), it is conceivable that tumors appearing in both knock-out strains reflect only ARF loss. However, there are some notable differences. (a) The mean latency for tumor formation was shorter in INK4a/ARF-nulls (32 weeks) versus ARF-null animals (38 weeks); following DMBA treatment, this trend was more exaggerated (12 weeks for INK4a/ARF-nulls versus 24 weeks for ARF-nulls). Moreover, we observed a significant number of carcinomas and neural tumors in the ARF-null animals that were not seen in untreated animals lacking INK4a/ARF. These differences may simply be due to founder effects; as in both cases, a single embryonic stem cell clone was used to generate germ-line chimeras. On the other hand, it may prove that p16INK4a loss in addition to p19ARF loss can further accelerate tumorigenesis, thereby shifting the tumor spectrum toward earlier arising sarcomas and lymphomas. Given that both INK4a and ARF loss are likely to contribute to human cancers through their functional interactions with the Rb and p53 pathways, respectively, clarification of phenotypic differences in mice, if any, will necessarily await the derivation of a knockout strain lacking INK4a alone.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported in part by NIH Cancer Center Core Grant CA-21765 and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. C. J. S. is an Investigator of the Howard Hughes Medical Institute. 
2 To whom requests for reprints should be addressed, at St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: (901) 495-3505; Fax: (901) 495-2381; E-mail: sherr{at}stjude.org
3 The abbreviation used is DMBA, dimethylbenzanthrene.
4 J. Weber, L. J. Taylor, M. F. Roussel, C. J. Sherr, and D. Bar-Sagi, unpublished data.
Received 3/ 2/99. Accepted 3/19/99.
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K. Kannan, N. E. Sharpless, J. Xu, R. C. O'Hagan, M. Bosenberg, and L. Chin Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model PNAS, February 4, 2003; 100(3): 1221 - 1225. [Abstract] [Full Text] [PDF]
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K. Y. Tsai, D. MacPherson, D. A. Rubinson, A. Yu. Nikitin, R. Bronson, K. L. Mercer, D. Crowley, and T. Jacks ARF mutation accelerates pituitary tumor development in Rb+/- mice PNAS, December 24, 2002; 99(26): 16865 - 16870. [Abstract] [Full Text] [PDF]
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A. Datta, A. Nag, and P. Raychaudhuri Differential Regulation of E2F1, DP1, and the E2F1/DP1 Complex by ARF Mol. Cell. Biol., December 15, 2002; 22(24): 8398 - 8408. [Abstract] [Full Text] [PDF]
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P. J. Houghton, P. C. Adamson, S. Blaney, H. A. Fine, R. Gorlick, M. Haber, L. Helman, S. Hirschfeld, M. G. Hollingshead, M. A. Israel, et al. Testing of New Agents in Childhood Cancer Preclinical Models: Meeting Summary Clin. Cancer Res., December 1, 2002; 8(12): 3646 - 3657. [Abstract] [Full Text] [PDF]
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Md. K. Hasan, T. Yaguchi, T. Sugihara, P. K. R. Kumar, K. Taira, R. R. Reddel, S. C. Kaul, and R. Wadhwa CARF Is a Novel Protein That Cooperates with Mouse p19ARF (Human p14ARF) in Activating p53 J. Biol. Chem., September 27, 2002; 277(40): 37765 - 37770. [Abstract] [Full Text] [PDF]
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C. M. Eischen, J. E. Rehg, S. J. Korsmeyer, and J. L. Cleveland Loss of Bax Alters Tumor Spectrum and Tumor Numbers in ARF-deficient Mice Cancer Res., April 1, 2002; 62(7): 2184 - 2191. [Abstract] [Full Text] [PDF]
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R. N. McKeller, J. L. Fowler, J. J. Cunningham, N. Warner, R. J. Smeyne, F. Zindy, and S. X. Skapek The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development PNAS, March 19, 2002; 99(6): 3848 - 3853. [Abstract] [Full Text] [PDF]
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J. L. Russell, J. T. Powers, R. J. Rounbehler, P. M. Rogers, C. J. Conti, and D. G. Johnson ARF Differentially Modulates Apoptosis Induced by E2F1 and Myc Mol. Cell. Biol., March 1, 2002; 22(5): 1360 - 1368. [Abstract] [Full Text] [PDF]
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K. Inoue, F. Zindy, D. H. Randle, J. E. Rehg, and C. J. Sherr Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas Genes & Dev., November 15, 2001; 15(22): 2934 - 2939. [Abstract] [Full Text] [PDF]
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M. Nakamura, T. Sakaki, H. Hashimoto, H. Nakase, E. Ishida, K. Shimada, and N. Konishi Frequent Alterations of the p14ARF and p16INK4a Genes in Primary Central Nervous System Lymphomas Cancer Res., September 1, 2001; 61(17): 6335 - 6339. [Abstract] [Full Text] [PDF]
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J. Martin-Caballero, J. M. Flores, P. Garcia-Palencia, and M. Serrano Tumor Susceptibility of p21Waf1/Cip1-deficient Mice Cancer Res., August 1, 2001; 61(16): 6234 - 6238. [Abstract] [Full Text] [PDF]
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S. A. Nicholson, N. T. Okby, M. A. Khan, J. A. Welsh, M. G. McMenamin, W. D. Travis, J. R. Jett, H. D. Tazelaar, V. Trastek, P. C. Pairolero, et al. Alterations of p14ARF, p53, and p73 Genes Involved in the E2F-1-mediated Apoptotic Pathways in Non-Small Cell Lung Carcinoma Cancer Res., July 1, 2001; 61(14): 5636 - 5643. [Abstract] [Full Text] [PDF]
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 T. K. Said, R. C. B. Moraes, U. Singh, F. S. Kittrell, and D. Medina Cyclin-dependent Kinase (cdk) Inhibitors/cdk4/cdk2 Complexes in Early Stages of Mouse Mammary Preneoplasia Cell Growth Differ., June 1, 2001; 12(6): 285 - 295. [Abstract] [Full Text] [PDF]
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E. A. Maher, F. B. Furnari, R. M. Bachoo, D. H. Rowitch, D. N. Louis, W. K. Cavenee, and R. A. DePinho Malignant glioma: genetics and biology of a grave matter Genes & Dev., June 1, 2001; 15(11): 1311 - 1333. [Full Text] [PDF]
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F. Zindy, W. den Besten, B. Chen, J. E. Rehg, E. Latres, M. Barbacid, J. W. Pollard, C. J. Sherr, P. E. Cohen, and M. F. Roussel Control of Spermatogenesis in Mice by the Cyclin D-Dependent Kinase Inhibitors p18Ink4c and p19Ink4d Mol. Cell. Biol., May 1, 2001; 21(9): 3244 - 3255. [Abstract] [Full Text]
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H. Ding, L. Roncari, P. Shannon, X. Wu, N. Lau, J. Karaskova, D. H. Gutmann, J. A. Squire, A. Nagy, and A. Guha Astrocyte-specific Expression of Activated p21-ras Results in Malignant Astrocytoma Formation in a Transgenic Mouse Model of Human Gliomas Cancer Res., May 1, 2001; 61(9): 3826 - 3836. [Abstract] [Full Text]
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A. W. Lin and S. W. Lowe Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation PNAS, April 12, 2001; (2001) 91100298. [Abstract] [Full Text]
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N. Bardeesy, B. C. Bastian, A. Hezel, D. Pinkel, R. A. DePinho, and L. Chin Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas Mol. Cell. Biol., March 15, 2001; 21(6): 2144 - 2153. [Abstract] [Full Text]
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C. Wetmore, D. E. Eberhart, and T. Curran Loss of p53 but not ARF Accelerates Medulloblastoma in Mice Heterozygous for patched Cancer Res., January 1, 2001; 61(2): 513 - 516. [Abstract] [Full Text]
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 C. Kuperwasser, G. D. Hurlbut, F. S. Kittrell, E. S. Dickinson, R. Laucirica, D. Medina, S. P. Naber, and D. J. Jerry Development of Spontaneous Mammary Tumors in BALB/c p53 Heterozygous Mice : A Model for Li-Fraumeni Syndrome Am. J. Pathol., December 1, 2000; 157(6): 2151 - 2159. [Abstract] [Full Text] [PDF]
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S. Zheng, P. Chen, A. McMillan, A. Lafuente, M. J. Lafuente, A. Ballesta, M. Trias, and J. K. Wiencke Correlations of partial and extensive methylation at the p14ARF locus with reduced mRNA expression in colorectal cancer cell lines and clinicopathological features in primary tumors Carcinogenesis, November 1, 2000; 21(11): 2057 - 2064. [Abstract] [Full Text] [PDF]
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H. H. A. Chao, A. M. Buchmann, and J. A. DeCaprio Loss of p19ARF Eliminates the Requirement for the pRB-Binding Motif in Simian Virus 40 Large T Antigen-Mediated Transformation Mol. Cell. Biol., October 15, 2000; 20(20): 7624 - 7633. [Abstract] [Full Text]
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J. D. Weber, J. R. Jeffers, J. E. Rehg, D. H. Randle, G. Lozano, M. F. Roussel, C. J. Sherr, and G. P. Zambetti p53-independent functions of the p19ARF tumor suppressor Genes & Dev., September 15, 2000; 14(18): 2358 - 2365. [Abstract] [Full Text]
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K. Inoue, R. Wen, J. E. Rehg, M. Adachi, J. L. Cleveland, M. F. Roussel, and C. J. Sherr Disruption of the ARF transcriptional activator DMP1 facilitates cell immortalization, Ras transformation, and tumorigenesis Genes & Dev., July 15, 2000; 14(14): 1797 - 1809. [Abstract] [Full Text]
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C. J. Sherr The Pezcoller Lecture: Cancer Cell Cycles Revisited Cancer Res., July 1, 2000; 60(14): 3689 - 3695. [Abstract] [Full Text]
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M. Pinyol, L. Hernandez, A. Martinez, F. Cobo, S. Hernandez, S. Bea, A. Lopez-Guillermo, I. Nayach, A. Palacin, A. Nadal, et al. INK4a/ARF Locus Alterations in Human Non-Hodgkin's Lymphomas Mainly Occur in Tumors with Wild-Type p53 Gene Am. J. Pathol., June 1, 2000; 156(6): 1987 - 1996. [Abstract] [Full Text] [PDF]
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M. Serrano The INK4a/ARF locus in murine tumorigenesis Carcinogenesis, May 1, 2000; 21(5): 865 - 869. [Abstract] [Full Text] [PDF]
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S. Marino, M. Vooijs, H. van der Gulden, J. Jonkers, and A. Berns Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum Genes & Dev., April 15, 2000; 14(8): 994 - 1004. [Abstract] [Full Text]
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J. D. Weber, M.-L. Kuo, B. Bothner, E. L. DiGiammarino, R. W. Kriwacki, M. F. Roussel, and C. J. Sherr Cooperative Signals Governing ARF-Mdm2 Interaction and Nucleolar Localization of the Complex Mol. Cell. Biol., April 1, 2000; 20(7): 2517 - 2528. [Abstract] [Full Text]
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M. Iwato, O. Tachibana, Y. Tohma, Y. Arakawa, H. Nitta, M. Hasegawa, J. Yamashita, and Y. Hayashi Alterations of the INK4a/ARF Locus in Human Intracranial Germ Cell Tumors Cancer Res., April 1, 2000; 60(8): 2113 - 2115. [Abstract] [Full Text]
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 W. N. ROM, J. G. HAY, T. C. LEE, Y. JIANG, and K.-M. TCHOU-WONG Molecular and Genetic Aspects of Lung Cancer Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1355 - 1367. [Full Text]
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G. WAHL and O. VAFA Genetic Instability, Oncogenes, and the p53 Pathway Cold Spring Harb Symp Quant Biol, January 1, 2000; 65(0): 511 - 520. [Abstract] [PDF]
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K. Ichimura, M. B. Bolin, H. M. Goike, E. E. Schmidt, A. Moshref, and V. P. Collins Deregulation of the p14ARF/MDM2/p53 Pathway Is a Prerequisite for Human Astrocytic Gliomas with G1-S Transition Control Gene Abnormalities Cancer Res., January 1, 2000; 60(2): 417 - 424. [Abstract] [Full Text]
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 K. S. Vogel, L. J. Klesse, S. Velasco-Miguel, K. Meyers, E. J. Rushing, and L. F. Parada Mouse Tumor Model for Neurofibromatosis Type 1 Science, December 10, 1999; 286(5447): 2176 - 2179. [Abstract] [Full Text]
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C. M. Eischen, J. D. Weber, M. F. Roussel, C. J. Sherr, and J. L. Cleveland Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis Genes & Dev., October 15, 1999; 13(20): 2658 - 2669. [Abstract] [Full Text]
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A. W. Lin and S. W. Lowe Oncogenic ras activates the ARF-p53 pathway to suppress epithelial cell transformation PNAS, April 24, 2001; 98(9): 5025 - 5030. [Abstract] [Full Text] [PDF]
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