| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Molecular Biology, Pathobiology and Genetics |
1 The Wistar Institute, Philadelphia, Pennsylvania and 2 Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California
Requests for reprints: Anthony J. Capobianco, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: 215-495-6816; Fax: 215-495-6819; E-mail: acapobianco{at}wistar.upenn.edu.
Aberrant Notch signaling contributes to more than half of all human T-cell leukemias, and accumulating evidence indicates Notch involvement in other human neoplasms. We developed a tetracycline-inducible mouse model (Top-Notchic) to examine the genetic interactions underlying the development of Notch-induced neoplastic disease. Using this model, we show that Notch suppresses p53 in lymphomagenesis through repression of the ARF-mdm2-p53 tumor surveillance network. Attenuation of Notch expression resulted in a dramatic increase in p53 levels that led to tumor regression by an apoptotic program. This shows that continued Notch activity is required to maintain the disease state. However, all tumors relapsed with rapid kinetics, most of which, by reactivation of Notch expression. Furthermore, by directly inhibiting the mdm2-p53 interaction by using either ionizing radiation or the novel small molecule therapeutic Nutlin, p53 can be activated and cause tumor cell death, even in the presence of sustained Notch activity. Therefore, it is the suppression of p53 that provides the Achilles heel for Notch-induced tumors, as activation of p53 in the presence of Notch signaling drives tumor regression. Our study provides proof-of-principle for the rational targeting of therapeutics against the mdm2-p53 pathway in Notch-induced neoplasms. Furthermore, we propose that suppression of p53 by Notch is a key mechanism underlying the initiation of T-cell lymphoma.
This article has been cited by other articles:
|
|
 |
|
  E. J. Volanakis, R. T. Williams, and C. J. Sherr Stage-specific Arf tumor suppression in Notch1-induced T-cell acute lymphoblastic leukemia Blood, November 12, 2009; 114(20): 4451 - 4459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Meurette, S. Stylianou, R. Rock, G. M. Collu, A. P. Gilmore, and K. Brennan Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells Cancer Res., June 15, 2009; 69(12): 5015 - 5022. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Wang, R. Qi, N. Li, Z. Wang, H. An, Q. Zhang, Y. Yu, and X. Cao Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression J. Biol. Chem., June 12, 2009; 284(24): 16183 - 16190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Dai Notch Signaling and Cancer Am. Assoc. Cancer Res. Educ. Book, April 18, 2009; 2009(1): 71 - 79. [Full Text] [PDF]
|
|
|
|
|
|
I. Joshi, L. M. Minter, J. Telfer, R. M. Demarest, A. J. Capobianco, J. C. Aster, P. Sicinski, A. Fauq, T. E. Golde, and B. A. Osborne Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases Blood, February 19, 2009; 113(8): 1689 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Palomero and A. Ferrando Oncogenic NOTCH1 Control of MYC and PI3K: Challenges and Opportunities for Anti-NOTCH1 Therapy in T-Cell Acute Lymphoblastic Leukemias and Lymphomas Clin. Cancer Res., September 1, 2008; 14(17): 5314 - 5317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Rizzo, H. Miao, G. D'Souza, C. Osipo, J. Yun, H. Zhao, J. Mascarenhas, D. Wyatt, G. Antico, L. Hao, et al. Cross-talk between Notch and the Estrogen Receptor in Breast Cancer Suggests Novel Therapeutic Approaches Cancer Res., July 1, 2008; 68(13): 5226 - 5235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Lee, C. M. Raskett, I. Prudovsky, and D. C. Altieri Molecular Dependence of Estrogen Receptor-Negative Breast Cancer on a Notch-Survivin Signaling Axis Cancer Res., July 1, 2008; 68(13): 5273 - 5281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. W. Purow, T. K. Sundaresan, M. J. Burdick, B. A. Kefas, L. D. Comeau, M. P. Hawkinson, Q. Su, Y. Kotliarov, J. Lee, W. Zhang, et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53 Carcinogenesis, May 1, 2008; 29(5): 918 - 925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Matsuoka, Y. Oike, I. Onoyama, A. Iwama, F. Arai, K. Takubo, Y. Mashimo, H. Oguro, E. Nitta, K. Ito, et al. Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL Genes & Dev., April 15, 2008; 22(8): 986 - 991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Podsypanina, K. Politi, L. J. Beverly, and H. E. Varmus Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras PNAS, April 1, 2008; 105(13): 5242 - 5247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Spaulding, E. J. Reschly, D. E. Zagort, Y. Yashiro-Ohtani, L. J. Beverly, A. Capobianco, W. S. Pear, and B. L. Kee Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas Blood, October 1, 2007; 110(7): 2650 - 2658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Lefort, A. Mandinova, P. Ostano, V. Kolev, V. Calpini, I. Kolfschoten, V. Devgan, J. Lieb, W. Raffoul, D. Hohl, et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK{alpha} kinases Genes & Dev., March 1, 2007; 21(5): 562 - 577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Sharma, J. A. Calvo, K. M. Draheim, L. A. Cunningham, N. Hermance, L. Beverly, V. Krishnamoorthy, M. Bhasin, A. J. Capobianco, and M. A. Kelliher Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc Mol. Cell. Biol., November 1, 2006; 26(21): 8022 - 8031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Reschly, C. Spaulding, T. Vilimas, W. V. Graham, R. L. Brumbaugh, I. Aifantis, W. S. Pear, and B. L. Kee Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and -independent mechanisms Blood, May 15, 2006; 107(10): 4115 - 4121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. G. Leong and A. Karsan Recent insights into the role of Notch signaling in tumorigenesis Blood, March 15, 2006; 107(6): 2223 - 2233. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
