Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 103 (6): 1888-1893

Copyright © 2006 by the National Academy of Sciences.

From the Cover


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy

Christian Tovar*,{dagger}, James Rosinski*,{dagger}, Zoran Filipovic*, Brian Higgins*, Kenneth Kolinsky*, Holly Hilton*, Xiaolan Zhao*, Binh T. Vu*, Weiguo Qing*, Kathryn Packman*, Ola Myklebost{ddagger}, David C. Heimbrook*, and Lyubomir T. Vassilev*,

*Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110; and {ddagger}Institute for Cancer Research, Norwegian Radium Hospital, 0310 Oslo, Norway

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved December 9, 2005

Received for publication August 28, 2005.

Abstract Back to Top

Abstract: The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53–MDM2 interaction.

Key Words: apoptosis • inhibitor • cell cycle • tumor • xenograft


Footnotes Back to Top

See Commentary on page 1659.

{dagger}C.T. and J.R. contributed equally to this work.

Author contributions: C.T., J.R., W.Q., K.P., and L.T.V. designed research; C.T., J.R., Z.F., B.H., K.K., H.H., X.Z., and L.T.V. performed research; B.T.V. and O.M. contributed new reagents/analytic tools; C.T., J.R., H.H., B.T.V., W.Q., K.P., O.M., D.C.H., and L.T.V. analyzed data; and O.M., D.C.H., and L.T.V. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

To whom correspondence should be addressed. E-mail: lyubomir.vassilev{at}roche.com

© 2006 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Nutlin-3a Efficacy in Sarcoma Predicted by Transcriptomic and Epigenetic Profiling.
K. I. Pishas, S. J. Neuhaus, M. T. Clayer, A. W. Schreiber, D. M. Lawrence, M. Perugini, R. J. Whitfield, G. Farshid, J. Manavis, S. Chryssidis, et al. (2014)
Cancer Res. 74, 921-931
   Abstract »    Full Text »    PDF »
Repurposing CRISPR/Cas9 for in situ functional assays.
A. Malina, J. R. Mills, R. Cencic, Y. Yan, J. Fraser, L. M. Schippers, M. Paquet, J. Dostie, and J. Pelletier (2013)
Genes & Dev. 27, 2602-2614
   Abstract »    Full Text »    PDF »
Stapled {alpha}-helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.
Y. S. Chang, B. Graves, V. Guerlavais, C. Tovar, K. Packman, K.-H. To, K. A. Olson, K. Kesavan, P. Gangurde, A. Mukherjee, et al. (2013)
PNAS 110, E3445-E3454
   Abstract »    Full Text »    PDF »
NF-{kappa}B Regulates Radioresistance Mediated By {beta}1-Integrin in Three-Dimensional Culture of Breast Cancer Cells.
K. M. Ahmed, H. Zhang, and C. C. Park (2013)
Cancer Res. 73, 3737-3748
   Abstract »    Full Text »    PDF »
RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an E{mu}-myc/Bcl-2 mouse model.
J. R. Mills, A. Malina, T. Lee, D. Di Paola, O. Larsson, C. Miething, F. Grosse, H. Tang, M. Zannis-Hadjopoulos, S. W. Lowe, et al. (2013)
Blood 121, 3402-3412
   Abstract »    Full Text »    PDF »
MDM2 Small-Molecule Antagonist RG7112 Activates p53 Signaling and Regresses Human Tumors in Preclinical Cancer Models.
C. Tovar, B. Graves, K. Packman, Z. Filipovic, B. H. M. Xia, C. Tardell, R. Garrido, E. Lee, K. Kolinsky, K.-H. To, et al. (2013)
Cancer Res. 73, 2587-2597
   Abstract »    Full Text »    PDF »
The DNA repair protein ALKBH2 mediates temozolomide resistance in human glioblastoma cells.
T.-C. A. Johannessen, L. Prestegarden, A. Grudic, M. E. Hegi, B. B. Tysnes, and R. Bjerkvig (2013)
Neuro Oncology 15, 269-278
   Abstract »    Full Text »    PDF »
A Fluorescent-Based High-Throughput Screening Assay for Small Molecules That Inhibit the Interaction of MdmX with p53.
K. Tsuganezawa, Y. Nakagawa, M. Kato, S. Taruya, F. Takahashi, M. Endoh, R. Utata, M. Mori, N. Ogawa, T. Honma, et al. (2013)
J Biomol Screen 18, 191-198
   Abstract »    Full Text »    PDF »
The impact of post-transcriptional regulation in the p53 network.
J. A. Freeman and J. M. Espinosa (2013)
Briefings in Functional Genomics 12, 46-57
   Abstract »    Full Text »    PDF »
Attractor Landscape Analysis Reveals Feedback Loops in the p53 Network That Control the Cellular Response to DNA Damage.
M. Choi, J. Shi, S. H. Jung, X. Chen, and K.-H. Cho (2012)
Science Signaling 5, ra83
   Abstract »    Full Text »    PDF »
Lithocholic acid is an endogenous inhibitor of MDM4 and MDM2.
S. M. Vogel, M. R. Bauer, A. C. Joerger, R. Wilcken, T. Brandt, D. B. Veprintsev, T. J. Rutherford, A. R. Fersht, and F. M. Boeckler (2012)
PNAS 109, 16906-16910
   Abstract »    Full Text »    PDF »
p53, a Target of Estrogen Receptor (ER) {alpha}, Modulates DNA Damage-induced Growth Suppression in ER-positive Breast Cancer Cells.
C. E. Berger, Y. Qian, G. Liu, H. Chen, and X. Chen (2012)
J. Biol. Chem. 287, 30117-30127
   Abstract »    Full Text »    PDF »
MDM2 inhibitor Nutlin-3a suppresses proliferation and promotes apoptosis in osteosarcoma cells.
B. Wang, L. Fang, H. Zhao, T. Xiang, and D. Wang (2012)
Acta Biochim Biophys Sin 44, 685-691
   Abstract »    Full Text »    PDF »
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization.
B. Graves, T. Thompson, M. Xia, C. Janson, C. Lukacs, D. Deo, P. Di Lello, D. Fry, C. Garvie, K.-S. Huang, et al. (2012)
PNAS 109, 11788-11793
   Abstract »    Full Text »    PDF »
Pharmacological activation of the p53 pathway by nutlin-3 exerts anti-tumoral effects in medulloblastomas.
A. Kunkele, K. De Preter, L. Heukamp, T. Thor, K. W. Pajtler, W. Hartmann, M. Mittelbronn, M. A. Grotzer, H. E. Deubzer, F. Speleman, et al. (2012)
Neuro Oncology 14, 859-869
   Abstract »    Full Text »    PDF »
p53 Dynamics Control Cell Fate.
J. E. Purvis, K. W. Karhohs, C. Mock, E. Batchelor, A. Loewer, and G. Lahav (2012)
Science 336, 1440-1444
   Abstract »    Full Text »    PDF »
p53 Pathway and Cancer Therapy.
D. P. Lane and C. F. Cheok (2012)
Am. Assoc. Cancer Res. Educ. Book 2012, 171-176
   Full Text »    PDF »
A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX.
R. E. Henry, Z. Andrysik, R. Paris, M. D. Galbraith, and J. M. Espinosa (2012)
EMBO J. 31, 1266-1278
   Abstract »    Full Text »    PDF »
Splicing Up Mdm2 for Cancer Proteome Diversity.
D. R. Okoro, M. Rosso, and J. Bargonetti (2012)
Genes & Cancer 3, 311-319
   Abstract »    Full Text »    PDF »
Tumor Suppressive MicroRNAs miR-34a/c Control Cancer Cell Expression of ULBP2, a Stress-Induced Ligand of the Natural Killer Cell Receptor NKG2D.
A. Heinemann, F. Zhao, S. Pechlivanis, J. Eberle, A. Steinle, S. Diederichs, D. Schadendorf, and A. Paschen (2012)
Cancer Res. 72, 460-471
   Abstract »    Full Text »    PDF »
Inhibition of MDM2 attenuates neointimal hyperplasia via suppression of vascular proliferation and inflammation.
T. Hashimoto, T. Ichiki, J. Ikeda, E. Narabayashi, H. Matsuura, R. Miyazaki, K. Inanaga, K. Takeda, and K. Sunagawa (2011)
Cardiovasc Res 91, 711-719
   Abstract »    Full Text »    PDF »
HMGA2 and p14Arf: Major Roles in Cellular Senescence of Fibroids and Therapeutic Implications.
D. N. MARKOWSKI, B. M. HELMKE, G. BELGE, R. NIMZYK, S. BARTNITZKE, U. DEICHERT, and J. BULLERDIEK (2011)
Anticancer Res 31, 753-761
   Abstract »    Full Text »    PDF »
Structural and Functional Comparison of the RING Domains of Two p53 E3 Ligases, Mdm2 and Pirh2.
J. Shloush, J. E. Vlassov, I. Engson, S. Duan, V. Saridakis, S. Dhe-paganon, B. Raught, Y. Sheng, and C. H. Arrowsmith (2011)
J. Biol. Chem. 286, 4796-4808
   Abstract »    Full Text »    PDF »
The p53 Pathway as a Target in Cancer Therapeutics: Obstacles and Promise.
A. Mandinova and S. W. Lee (2011)
Science Translational Medicine 3, 64rv1
   Full Text »    PDF »
MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response.
M. Petroni, V. Veschi, A. Prodosmo, C. Rinaldo, I. Massimi, M. Carbonari, C. Dominici, H. P. McDowell, C. Rinaldi, I. Screpanti, et al. (2011)
Mol. Cancer Res. 9, 67-77
   Abstract »    Full Text »    PDF »
Coactivated Platelet-Derived Growth Factor Receptor {alpha} and Epidermal Growth Factor Receptor Are Potential Therapeutic Targets in Intimal Sarcoma.
B. Dewaele, G. Floris, J. Finalet-Ferreiro, C. D. Fletcher, J.-M. Coindre, L. Guillou, P. C. W. Hogendoorn, A. Wozniak, V. Vanspauwen, P. Schoffski, et al. (2010)
Cancer Res. 70, 7304-7314
   Abstract »    Full Text »    PDF »
Implementation of a 220,000-Compound HCS Campaign to Identify Disruptors of the Interaction between p53 and hDM2 and Characterization of the Confirmed Hits.
D. D. Dudgeon, S. Shinde, Y. Hua, T. Y. Shun, J. S. Lazo, C. J. Strock, K. A. Giuliano, D. L. Taylor, P. A. Johnston, and P. A. Johnston (2010)
J Biomol Screen 15, 766-782
   Abstract »    Full Text »    PDF »
Persistent p21 Expression after Nutlin-3a Removal Is Associated with Senescence-like Arrest in 4N Cells.
H. Shen and C. G. Maki (2010)
J. Biol. Chem. 285, 23105-23114
   Abstract »    Full Text »    PDF »
Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia.
J. Long, B. Parkin, P. Ouillette, D. Bixby, K. Shedden, H. Erba, S. Wang, and S. N. Malek (2010)
Blood 116, 71-80
   Abstract »    Full Text »    PDF »
Transcriptional Switches: Chemical Approaches to Gene Regulation.
L. W. Lee and A. K. Mapp (2010)
J. Biol. Chem. 285, 11033-11038
   Abstract »    Full Text »    PDF »
Identification and Characterization of the First Small Molecule Inhibitor of MDMX.
D. Reed, Y. Shen, A. A. Shelat, L. A. Arnold, A. M. Ferreira, F. Zhu, N. Mills, D. C. Smithson, C. A. Regni, D. Bashford, et al. (2010)
J. Biol. Chem. 285, 10786-10796
   Abstract »    Full Text »    PDF »
Nutlin-3a Induces Cytoskeletal Rearrangement and Inhibits the Migration and Invasion Capacity of p53 Wild-Type Cancer Cells.
D. M. Moran and C. G. Maki (2010)
Mol. Cancer Ther. 9, 895-905
   Abstract »    Full Text »    PDF »
Pharmacological activation of the p53 pathway in haematological malignancies.
M. N Saha, J. Micallef, L. Qiu, and H. Chang (2010)
J. Clin. Pathol. 63, 204-209
   Abstract »    Full Text »    PDF »
Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib.
M. G. Ooi, P. J. Hayden, V. Kotoula, D. W. McMillin, E. Charalambous, E. Daskalaki, N. S. Raje, N. C. Munshi, D. Chauhan, T. Hideshima, et al. (2009)
Clin. Cancer Res. 15, 7153-7160
   Abstract »    Full Text »    PDF »
Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53.
T. Van Maerken, L. Ferdinande, J. Taildeman, I. Lambertz, N. Yigit, L. Vercruysse, A. Rihani, M. Michaelis, J. Cinatl Jr, C. A. Cuvelier, et al. (2009)
J Natl Cancer Inst 101, 1562-1574
   Abstract »    Full Text »    PDF »
Nutlin-3 Affects Expression and Function of Retinoblastoma Protein: ROLE OF RETINOBLASTOMA PROTEIN IN CELLULAR RESPONSE TO NUTLIN-3.
W. Du, J. Wu, E. M. Walsh, Y. Zhang, C. Y. Chen, and Z.-X. J. Xiao (2009)
J. Biol. Chem. 284, 26315-26321
   Abstract »    Full Text »    PDF »
Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells.
B. Huang, D. Deo, M. Xia, and L. T. Vassilev (2009)
Mol. Cancer Res. 7, 1497-1509
   Abstract »    Full Text »    PDF »
HIPK2 Regulation by MDM2 Determines Tumor Cell Response to the p53-Reactivating Drugs Nutlin-3 and RITA.
C. Rinaldo, A. Prodosmo, F. Siepi, A. Moncada, A. Sacchi, G. Selivanova, and S. Soddu (2009)
Cancer Res. 69, 6241-6248
   Abstract »    Full Text »    PDF »
Restoration of p53 Pathway by Nutlin-3 Induces Cell Cycle Arrest and Apoptosis in Human Rhabdomyosarcoma Cells.
M. Miyachi, N. Kakazu, S. Yagyu, Y. Katsumi, S. Tsubai-Shimizu, K. Kikuchi, K. Tsuchiya, T. Iehara, and H. Hosoi (2009)
Clin. Cancer Res. 15, 4077-4084
   Abstract »    Full Text »    PDF »
Heat shock factor-1 modulates p53 activity in the transcriptional response to DNA damage.
I. R. Logan, H. V. McNeill, S. Cook, X. Lu, D. W. Meek, F. V. Fuller-Pace, J. Lunec, and C. N. Robson (2009)
Nucleic Acids Res. 37, 2962-2973
   Abstract »    Full Text »    PDF »
Small-Molecule Activation of p53 Blocks Hypoxia-Inducible Factor 1{alpha} and Vascular Endothelial Growth Factor Expression In Vivo and Leads to Tumor Cell Apoptosis in Normoxia and Hypoxia.
J. Yang, A. Ahmed, E. Poon, N. Perusinghe, A. de Haven Brandon, G. Box, M. Valenti, S. Eccles, K. Rouschop, B. Wouters, et al. (2009)
Mol. Cell. Biol. 29, 2243-2253
   Abstract »    Full Text »    PDF »
p53 Attenuates Lipopolysaccharide-Induced NF-{kappa}B Activation and Acute Lung Injury.
G. Liu, Y.-J. Park, Y. Tsuruta, E. Lorne, and E. Abraham (2009)
J. Immunol. 182, 5063-5071
   Abstract »    Full Text »    PDF »
MDM2-Dependent Inhibition of p53 Is Required for Epstein-Barr Virus B-Cell Growth Transformation and Infected-Cell Survival.
E. Forte and M. A. Luftig (2009)
J. Virol. 83, 2491-2499
   Abstract »    Full Text »    PDF »
Monocytic Leukemia Zinc Finger (MOZ) Interacts with p53 to Induce p21 Expression and Cell-cycle Arrest.
S. Rokudai, Y. Aikawa, Y. Tagata, N. Tsuchida, Y. Taya, and I. Kitabayashi (2009)
J. Biol. Chem. 284, 237-244
   Abstract »    Full Text »    PDF »
Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry?.
M. Wade and G. M. Wahl (2009)
Mol. Cancer Res. 7, 1-11
   Abstract »    Full Text »    PDF »
Functional proteomic profiling of AML predicts response and survival.
S. M. Kornblau, R. Tibes, Y. H. Qiu, W. Chen, H. M. Kantarjian, M. Andreeff, K. R. Coombes, and G. B. Mills (2009)
Blood 113, 154-164
   Abstract »    Full Text »    PDF »
Targeting the MDM2-p53 Interaction for Cancer Therapy.
S. Shangary and S. Wang (2008)
Clin. Cancer Res. 14, 5318-5324
   Abstract »    Full Text »    PDF »
SNP309 as predictor for sensitivity of CLL cells to the MDM2 inhibitor nutlin-3a.
I. Seyfried, S. Hofbauer, M. Stoecher, R. Greil, and I. Tinhofer (2008)
Blood 112, 2168
   Full Text »    PDF »
Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer.
S. Shangary, K. Ding, S. Qiu, Z. Nikolovska-Coleska, J. A. Bauer, M. Liu, G. Wang, Y. Lu, D. McEachern, D. Bernard, et al. (2008)
Mol. Cancer Ther. 7, 1533-1542
   Abstract »    Full Text »    PDF »
Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence.
K. Kumamoto, E. A. Spillare, K. Fujita, I. Horikawa, T. Yamashita, E. Appella, M. Nagashima, S. Takenoshita, J. Yokota, and C. C. Harris (2008)
Cancer Res. 68, 3193-3203
   Abstract »    Full Text »    PDF »
Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition.
S. Shangary, D. Qin, D. McEachern, M. Liu, R. S. Miller, S. Qiu, Z. Nikolovska-Coleska, K. Ding, G. Wang, J. Chen, et al. (2008)
PNAS 105, 3933-3938
   Abstract »    Full Text »    PDF »
Genotoxic Stress-Induced Expression of p53 and Apoptosis in Leukemic Clam Hemocytes with Cytoplasmically Sequestered p53.
S. Bottger, E. Jerszyk, B. Low, and C. Walker (2008)
Cancer Res. 68, 777-782
   Abstract »    Full Text »    PDF »
MDM2 Gene Amplification Is Correlated to Tumor Progression but not to the Presence of SNP309 or TP53 Mutational Status in Primary Colorectal Cancers.
A. Forslund, Z. Zeng, L.-X. Qin, S. Rosenberg, M. Ndubuisi, H. Pincas, W. Gerald, D. A. Notterman, F. Barany, and P. B. Paty (2008)
Mol. Cancer Res. 6, 205-211
   Abstract »    Full Text »    PDF »
Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia.
C. Saddler, P. Ouillette, L. Kujawski, S. Shangary, M. Talpaz, M. Kaminski, H. Erba, K. Shedden, S. Wang, and S. N. Malek (2008)
Blood 111, 1584-1593
   Abstract »    Full Text »    PDF »
Hsp27 Modulates p53 Signaling and Suppresses Cellular Senescence.
C. O'Callaghan-Sunol, V. L. Gabai, and M. Y. Sherman (2007)
Cancer Res. 67, 11779-11788
   Abstract »    Full Text »    PDF »
Efficient p53 Activation and Apoptosis by Simultaneous Disruption of Binding to MDM2 and MDMX.
B. Hu, D. M. Gilkes, and J. Chen (2007)
Cancer Res. 67, 8810-8817
   Abstract »    Full Text »    PDF »
Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway.
B. C. Bornhauser, L. Bonapace, D. Lindholm, R. Martinez, G. Cario, M. Schrappe, F. K. Niggli, B. W. Schafer, and J.-P. Bourquin (2007)
Blood 110, 2084-2091
   Abstract »    Full Text »    PDF »
Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin.
A. Efeyan, A. Ortega-Molina, S. Velasco-Miguel, D. Herranz, L. T. Vassilev, and M. Serrano (2007)
Cancer Res. 67, 7350-7357
   Abstract »    Full Text »    PDF »
Quantitative analyses reveal the importance of regulated Hdmx degradation for P53 activation.
Y. V. Wang, M. Wade, E. Wong, Y.-C. Li, L. W. Rodewald, and G. M. Wahl (2007)
PNAS 104, 12365-12370
   Abstract »    Full Text »    PDF »
Gene Expression Profiling of Liposarcoma Identifies Distinct Biological Types/Subtypes and Potential Therapeutic Targets in Well-Differentiated and Dedifferentiated Liposarcoma.
S. Singer, N. D. Socci, G. Ambrosini, E. Sambol, P. Decarolis, Y. Wu, R. O'Connor, R. Maki, A. Viale, C. Sander, et al. (2007)
Cancer Res. 67, 6626-6636
   Abstract »    Full Text »    PDF »
Loss of Mdm4 Results in p53-Dependent Dilated Cardiomyopathy.
S. Xiong, C. S. Van Pelt, A. C. Elizondo-Fraire, B. Fernandez-Garcia, and G. Lozano (2007)
Circulation 115, 2925-2930
   Abstract »    Full Text »    PDF »
Inhibition of p53-Murine Double Minute 2 Interaction by Nutlin-3A Stabilizes p53 and Induces Cell Cycle Arrest and Apoptosis in Hodgkin Lymphoma.
E. Drakos, A. Thomaides, L. J. Medeiros, J. Li, V. Leventaki, M. Konopleva, M. Andreeff, and G. Z. Rassidakis (2007)
Clin. Cancer Res. 13, 3380-3387
   Abstract »    Full Text »    PDF »
Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy.
C. E. Petre, S.-H. Sin, and D. P. Dittmer (2007)
J. Virol. 81, 1912-1922
   Abstract »    Full Text »    PDF »
Nutlin-3 Protects Kidney Cells during Cisplatin Therapy by Suppressing Bax/Bak Activation.
M. Jiang, N. Pabla, R. F. Murphy, T. Yang, X.-M. Yin, K. Degenhardt, E. White, and Z. Dong (2007)
J. Biol. Chem. 282, 2636-2645
   Abstract »    Full Text »    PDF »
An Antagonist of Dishevelled Protein-Protein Interaction Suppresses {beta}-Catenin-Dependent Tumor Cell Growth.
N. Fujii, L. You, Z. Xu, K. Uematsu, J. Shan, B. He, I. Mikami, L. R. Edmondson, G. Neale, J. Zheng, et al. (2007)
Cancer Res. 67, 573-579
   Abstract »    Full Text »    PDF »
A Novel Application for Murine Double Minute 2 Antagonists: The p53 Tumor Suppressor Network Also Controls Angiogenesis.
B. R. Binder (2007)
Circ. Res. 100, 13-14
   Full Text »    PDF »
An Organometallic Protein Kinase Inhibitor Pharmacologically Activates p53 and Induces Apoptosis in Human Melanoma Cells.
K. S.M. Smalley, R. Contractor, N. K. Haass, A. N. Kulp, G. E. Atilla-Gokcumen, D. S. Williams, H. Bregman, K. T. Flaherty, M. S. Soengas, E. Meggers, et al. (2007)
Cancer Res. 67, 209-217
   Abstract »    Full Text »    PDF »
p53 Attenuates Cancer Cell Migration and Invasion through Repression of SDF-1/CXCL12 Expression in Stromal Fibroblasts..
N. Moskovits, A. Kalinkovich, J. Bar, T. Lapidot, and M. Oren (2006)
Cancer Res. 66, 10671-10676
   Abstract »    Full Text »    PDF »
Hdmx Modulates the Outcome of P53 Activation in Human Tumor Cells.
M. Wade, E. T. Wong, M. Tang, J. M. Stommel, and G. M. Wahl (2006)
J. Biol. Chem. 281, 33036-33044
   Abstract »    Full Text »    PDF »
Nongenotoxic p53 Activation Protects Cells against S-Phase-Specific Chemotherapy.
D. Kranz and M. Dobbelstein (2006)
Cancer Res. 66, 10274-10280
   Abstract »    Full Text »    PDF »
A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization.
Y. Aylon, D. Michael, A. Shmueli, N. Yabuta, H. Nojima, and M. Oren (2006)
Genes & Dev. 20, 2687-2700
   Abstract »    Full Text »    PDF »
Posttranslational Protein Modifications: Current Implications for Cancer Detection, Prevention, and Therapeutics.
K. E. Krueger and S. Srivastava (2006)
Mol. Cell. Proteomics 5, 1799-1810
   Full Text »    PDF »
MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death..
E. Barbieri, P. Mehta, Z. Chen, L. Zhang, A. Slack, S. Berg, and J. M. Shohet (2006)
Mol. Cancer Ther. 5, 2358-2365
   Abstract »    Full Text »    PDF »
Protein-protein interactions for cancer therapy.
C. C. Harris (2006)
PNAS 103, 1659-1660
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882