This Article Full Text Full Text (PDF) Supplementary Data 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 Lawlor, E. R. Articles by Evan, G. I. Search for Related Content PubMed PubMed Citation Articles by Lawlor, E. R. Articles by Evan, G. I.

Reversible Kinetic Analysis of Myc Targets In vivo Provides Novel Insights into Myc-Mediated Tumorigenesis

Cancer Research Institute, University of California San Francisco Comprehensive Cancer Center, San Francisco, California

Requests for reprints: Gerard I. Evan, Cancer Research Institute, University of California San Francisco, Comprehensive Cancer Center, 2340 Sutter Street, San Francisco, CA 94143-0875. E-mail: gevan{at}cc.ucsf.edu or Elizabeth R. Lawlor, Children's Hospital Los Angeles, 4650 Sunset Boulevard MS57, Los Angeles, CA 90027. Phone: 323-644-8579; E-mail: elawlor{at}chla.usc.edu.

Deregulated expression of the Myc transcription factor is a frequent causal mutation in human cancer. Thousands of putative Myc target genes have been identified in in vitro studies, indicating that Myc exerts highly pleiotropic effects within cells and tissues. However, the complexity and diversity of Myc gene targets has confounded attempts at identifying which of these genes are the critical targets mediating Myc-driven tumorigenesis in vivo. Acute activation of Myc in a reversibly switchable transgenic model of Myc-mediated ß cell tumorigenesis induces rapid tumor onset, whereas subsequent Myc deactivation triggers equally rapid tumor regression. Thus, sustained Myc activity is required for tumor maintenance. We have used this reversibly switchable kinetic tumor model in combination with high-density oligonucleotide microarrays to develop an unbiased strategy for identifying candidate Myc-regulated genes responsible for maintenance of Myc-dependent tumors. Consistent with known Myc functions, some Myc-regulated genes are involved in cell growth, cycle, and proliferation. In addition, however, many Myc-regulated genes are specific to ß cells, indicating that a significant component of Myc action is cell type specific. Finally, we identify a very restricted cadre of genes with expression that is inversely regulated upon Myc activation-induced tumor progression and deactivation-induced tumor regression. By definition, such genes are candidates for tumor maintenance functions. Combining reversibly switchable, transgenic models of tumor formation and regression with genomic profiling offers a novel strategy with which to deconvolute the complexities of oncogenic signaling pathways in vivo. (Cancer Res 2006; 66(9): 4591-601)

This article has been cited by other articles:

				A. J. Finch, L. Soucek, M. R. Junttila, L. B. Swigart, and G. I. Evan Acute Overexpression of Myc in Intestinal Epithelium Recapitulates Some but Not All the Changes Elicited by Wnt/{beta}-Catenin Pathway Activation Mol. Cell. Biol., October 1, 2009; 29(19): 5306 - 5315. [Abstract] [Full Text] [PDF]

				A. Radziszewska, S. A. Schroer, D. Choi, P. Tajmir, N. Radulovich, J. C. Ho, L. Wang, N. Liadis, R. Hakem, M.-S. Tsao, et al. Absence of Caspase-3 Protects Pancreatic {beta}-Cells from c-Myc-induced Apoptosis without Leading to Tumor Formation J. Biol. Chem., April 17, 2009; 284(16): 10947 - 10956. [Abstract] [Full Text] [PDF]

				D. Garcia-Crespo, E. Knock, N. Jabado, and R. Rozen Intestinal Neoplasia Induced by Low Dietary Folate Is Associated with Altered Tumor Expression Profiles and Decreased Apoptosis in Mouse Normal Intestine J. Nutr., March 1, 2009; 139(3): 488 - 494. [Abstract] [Full Text] [PDF]

				D.-M. Shin, D. J. Shaffer, H. Wang, D. C. Roopenian, and H. C. Morse III NOTCH Is Part of the Transcriptional Network Regulating Cell Growth and Survival in Mouse Plasmacytomas Cancer Res., November 15, 2008; 68(22): 9202 - 9211. [Abstract] [Full Text] [PDF]

				M. Eilers and R. N. Eisenman Myc's broad reach Genes & Dev., October 15, 2008; 22(20): 2755 - 2766. [Abstract] [Full Text] [PDF]

				C. M. Shachaf, A. J. Gentles, S. Elchuri, D. Sahoo, Y. Soen, O. Sharpe, O. D. Perez, M. Chang, D. Mitchel, W. H. Robinson, et al. Genomic and Proteomic Analysis Reveals a Threshold Level of MYC Required for Tumor Maintenance Cancer Res., July 1, 2008; 68(13): 5132 - 5142. [Abstract] [Full Text] [PDF]

				D. A. Cano, I. C. Rulifson, P. W. Heiser, L. B. Swigart, S. Pelengaris, M. German, G. I. Evan, J. A. Bluestone, and M. Hebrok Regulated {beta}-Cell Regeneration in the Adult Mouse Pancreas Diabetes, April 1, 2008; 57(4): 958 - 966. [Abstract] [Full Text] [PDF]

				F. A. Mallette, M.-F. Gaumont-Leclerc, G. Huot, and G. Ferbeyre Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence J. Biol. Chem., November 30, 2007; 282(48): 34938 - 34944. [Abstract] [Full Text] [PDF]

				K. Shchors and G. Evan Tumor Angiogenesis: Cause or Consequence of Cancer? Cancer Res., August 1, 2007; 67(15): 7059 - 7061. [Abstract] [Full Text] [PDF]

				K. Shchors, E. Shchors, F. Rostker, E. R. Lawlor, L. Brown-Swigart, and G. I. Evan The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta Genes & Dev., September 15, 2006; 20(18): 2527 - 2538. [Abstract] [Full Text] [PDF]