This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kamijo, T. Articles by Sherr, C. J. Search for Related Content PubMed PubMed Citation Articles by Kamijo, T. Articles by Sherr, C. J.

Tumor Spectrum in ARF-deficient Mice¹

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

The p19^ARF product of the INK4a/ARF locus is induced in response to potentially oncogenic hyperproliferative signals and activates p53 by interfering with its negative regulator, Mdm2. Mice lacking ARF are highly prone to tumor development, and in this study, 80% of these animals spontaneously developed tumors and died within their first year of life. Mice that were heterozygous for ARF also developed tumors after a longer latency, whereas their wild-type littermates did not. In heterozygotes, tumor formation was accompanied by loss of the residual ARF allele and/or lack of ARF mRNA expression, implying that ARF can act as a canonical "two-hit" tumor suppressor gene. Tumors occurred earlier in life in ARF-null animals that were neonatally irradiated or given dimethylbenzanthrene, and several animals treated with carcinogen simultaneously developed multiple forms of malignancy arising from distinct cell lineages. Although p53-null mice primarily develop lymphomas and fibrosarcomas, the frequency of these two tumor types was inverted in ARF-null animals, with undifferentiated sarcomas predominating in a 3:2 ratio; 28% of ARF-null animals developed carcinomas and tumors of the nervous system, which have been rarely observed in untreated p53-null mice. The longer latency of tumor formation in ARF-null versus p53-null mice, therefore, appears to enable a broader spectrum of tumors to emerge.

This article has been cited by other articles:

				Z. Chen, A. Carracedo, H.-K. Lin, J. A. Koutcher, N. Behrendt, A. Egia, A. Alimonti, B. S. Carver, W. Gerald, J. Teruya-Feldstein, et al. Differential p53-Independent Outcomes of p19Arf Loss in Oncogenesis Sci. Signal., August 18, 2009; 2(84): ra44 - ra44. [Abstract] [Full Text] [PDF]

				E. L. Volk, L. Fan, K. Schuster, J. E. Rehg, and L. C. Harris The MDM2-A Splice Variant of MDM2 Alters Transformation In vitro and the Tumor Spectrum in Both Arf- and p53-Null Models of Tumorigenesis Mol. Cancer Res., June 1, 2009; 7(6): 863 - 869. [Abstract] [Full Text] [PDF]

				D. A. Altomare, C. W. Menges, J. Pei, L. Zhang, K. L. Skele-Stump, M. Carbone, A. B. Kane, and J. R. Testa Activated TNF-{alpha}/NF-{kappa}B signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice PNAS, March 3, 2009; 106(9): 3420 - 3425. [Abstract] [Full Text] [PDF]

				R. S. Zimmerman and N. Rosenberg Changes in p19Arf Localization Accompany Apoptotic Crisis during Pre-B-Cell Transformation by Abelson Murine Leukemia Virus J. Virol., September 1, 2008; 82(17): 8383 - 8391. [Abstract] [Full Text] [PDF]

				F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment Genes & Dev., November 1, 2007; 21(21): 2683 - 2710. [Abstract] [Full Text] [PDF]

				J. P. Morrison, H. Satoh, J. Foley, J. L. Horton, J. K. Dunnick, G. E. Kissling, and D. E. Malarkey N-ethyl-N-nitrosourea (ENU)-Induced Meningiomatosis and Meningioma in p16INK4a/p19ARF Tumor Suppressor Gene-Deficient Mice Toxicol Pathol, October 1, 2007; 35(6): 838 - 845. [Abstract] [Full Text] [PDF]

				S. Paliwal, R. C. Kovi, B. Nath, Y.-W. Chen, B. C. Lewis, and S. R. Grossman The Alternative Reading Frame Tumor Suppressor Antagonizes Hypoxia-Induced Cancer Cell Migration via Interaction with the COOH-Terminal Binding Protein Corepressor Cancer Res., October 1, 2007; 67(19): 9322 - 9329. [Abstract] [Full Text] [PDF]

				L. A. Fecher, S. D. Cummings, M. J. Keefe, and R. M. Alani Toward a Molecular Classification of Melanoma J. Clin. Oncol., April 20, 2007; 25(12): 1606 - 1620. [Abstract] [Full Text] [PDF]

				E. I. Fomchenko and E. C. Holland Mouse models of brain tumors and their applications in preclinical trials. Clin. Cancer Res., September 15, 2006; 12(18): 5288 - 5297. [Abstract] [Full Text] [PDF]

				Y. Shou, Z. Ma, T. Lu, and B. P. Sorrentino Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy PNAS, August 1, 2006; 103(31): 11730 - 11735. [Abstract] [Full Text] [PDF]

				S. E. Mercer, D. Z. Ewton, S. Shah, A. Naqvi, and E. Friedman Mirk/Dyrk1b mediates cell survival in rhabdomyosarcomas. Cancer Res., May 15, 2006; 66(10): 5143 - 5150. [Abstract] [Full Text] [PDF]

				D. A. Largaespada Improving Cancer Gene Screens: Insertional Mutagenesis Using Sleeping Beauty Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 24 - 28. [Full Text] [PDF]

				S. Paliwal, S. Pande, R. C. Kovi, N. E. Sharpless, N. Bardeesy, and S. R. Grossman Targeting of C-Terminal Binding Protein (CtBP) by ARF Results in p53-Independent Apoptosis Mol. Cell. Biol., March 15, 2006; 26(6): 2360 - 2372. [Abstract] [Full Text] [PDF]

				T. V. Kalin, I-C. Wang, T. J. Ackerson, M. L. Major, C. J. Detrisac, V. V. Kalinichenko, A. Lyubimov, and R. H. Costa Increased Levels of the FoxM1 Transcription Factor Accelerate Development and Progression of Prostate Carcinomas in both TRAMP and LADY Transgenic Mice Cancer Res., February 1, 2006; 66(3): 1712 - 1720. [Abstract] [Full Text] [PDF]

				C. M. Carlson, J. L. Frandsen, N. Kirchhof, R. S. McIvor, and D. A. Largaespada Somatic integration of an oncogene-harboring Sleeping Beauty transposon models liver tumor development in the mouse PNAS, November 22, 2005; 102(47): 17059 - 17064. [Abstract] [Full Text] [PDF]

				L. S. Collier and D. A. Largaespada Hopping around the Tumor Genome: Transposons for Cancer Gene Discovery Cancer Res., November 1, 2005; 65(21): 9607 - 9610. [Abstract] [Full Text] [PDF]

				T. Maeda, R. M. Hobbs, and P. P. Pandolfi The Transcription Factor Pokemon: A New Key Player in Cancer Pathogenesis Cancer Res., October 1, 2005; 65(19): 8575 - 8578. [Abstract] [Full Text] [PDF]

				H. Hanawa, D. A. Persons, and A. W. Nienhuis Mobilization and Mechanism of Transcription of Integrated Self-Inactivating Lentiviral Vectors J. Virol., July 1, 2005; 79(13): 8410 - 8421. [Abstract] [Full Text] [PDF]

				I. Perez de Castro, M. Benet, M. Jimenez, S. Alzabin, M. Malumbres, and A. Pellicer Mouse p10, an Alternative Spliced Form of p15INK4b, Inhibits Cell Cycle Progression and Malignant Transformation Cancer Res., April 15, 2005; 65(8): 3249 - 3256. [Abstract] [Full Text] [PDF]

				L. Uhrbom, M. Kastemar, F. K. Johansson, B. Westermark, and E. C. Holland Cell Type-Specific Tumor Suppression by Ink4a and Arf in Kras-Induced Mouse Gliomagenesis Cancer Res., March 15, 2005; 65(6): 2065 - 2069. [Abstract] [Full Text] [PDF]

				R. Meuwissen and A. Berns Mouse models for human lung cancer Genes & Dev., March 15, 2005; 19(6): 643 - 664. [Abstract] [Full Text] [PDF]

				R. Sreeramaneni, A. Chaudhry, M. McMahon, C. J. Sherr, and K. Inoue Ras-Raf-Arf Signaling Critically Depends on the Dmp1 Transcription Factor Mol. Cell. Biol., January 1, 2005; 25(1): 220 - 232. [Abstract] [Full Text] [PDF]

				C.J. SHERR, D. BERTWISTLE, W. DEN BESTEN, M.-L. KUO, M. SUGIMOTO, K. TAGO, R.T. WILLIAMS, F. ZINDY, and M.F. ROUSSEL p53-Dependent and -Independent Functions of the Arf Tumor Suppressor Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 129 - 137. [Abstract] [PDF]

				R. PARDAL, A.V. MOLOFSKY, S. HE, and S.J. MORRISON Stem Cell Self-Renewal and Cancer Cell Proliferation Are Regulated by Common Networks That Balance the Activation of Proto-oncogenes and Tumor Suppressors Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 177 - 185. [Abstract] [PDF]

				S. N. Brady, Y. Yu, L. B. Maggi Jr., and J. D. Weber ARF Impedes NPM/B23 Shuttling in an Mdm2-Sensitive Tumor Suppressor Pathway Mol. Cell. Biol., November 1, 2004; 24(21): 9327 - 9338. [Abstract] [Full Text] [PDF]

				R. Sandoval, J. Xue, M. Pilkinton, D. Salvi, H. Kiyokawa, and O. R. Colamonici Different Requirements for the Cytostatic and Apoptotic Effects of Type I Interferons: INDUCTION OF APOPTOSIS REQUIRES ARF BUT NOT p53 IN OSTEOSARCOMA CELL LINES J. Biol. Chem., July 30, 2004; 279(31): 32275 - 32280. [Abstract] [Full Text] [PDF]

				B. Calabretta and D. Perrotti The biology of CML blast crisis Blood, June 1, 2004; 103(11): 4010 - 4022. [Abstract] [Full Text] [PDF]

				Y. Yi, A. Shepard, F. Kittrell, B. Mulac-Jericevic, D. Medina, and T. K. Said p19ARF Determines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development Mol. Biol. Cell, May 1, 2004; 15(5): 2302 - 2311. [Abstract] [Full Text] [PDF]

				V. V. Kalinichenko, M. L. Major, X. Wang, V. Petrovic, J. Kuechle, H. M. Yoder, M. B. Dennewitz, B. Shin, A. Datta, P. Raychaudhuri, et al. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor Genes & Dev., April 1, 2004; 18(7): 830 - 850. [Abstract] [Full Text] [PDF]

				F. Zindy, R. T. Williams, T. A. Baudino, J. E. Rehg, S. X. Skapek, J. L. Cleveland, M. F. Roussel, and C. J. Sherr Arf tumor suppressor promoter monitors latent oncogenic signals in vivo PNAS, December 23, 2003; 100(26): 15930 - 15935. [Abstract] [Full Text] [PDF]

				T. Watanabe, Y. Katayama, A. Yoshino, C. Komine, and T. Yokoyama Deregulation of the TP53/p14ARF Tumor Suppressor Pathway in Low-Grade Diffuse Astrocytomas and Its Influence on Clinical Course Clin. Cancer Res., October 15, 2003; 9(13): 4884 - 4890. [Abstract] [Full Text] [PDF]

				V. Zoumpourlis, S. Solakidi, A. Papathoma, and D. Papaevangeliou Alterations in signal transduction pathways implicated in tumour progression during multistage mouse skin carcinogenesis Carcinogenesis, July 1, 2003; 24(7): 1159 - 1165. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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] [PDF]

				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]

				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]

				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] [PDF]

				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]

				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]

				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]

				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] [PDF]

				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]

				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]

				C. J. Sherr The Pezcoller Lecture: Cancer Cell Cycles Revisited Cancer Res., July 1, 2000; 60(14): 3689 - 3695. [Abstract] [Full Text]

				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]

				M. Serrano The INK4a/ARF locus in murine tumorigenesis Carcinogenesis, May 1, 2000; 21(5): 865 - 869. [Abstract] [Full Text] [PDF]

				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]

				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] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]