This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Sheng, H. Articles by Dlugosz, A. A. Search for Related Content PubMed PubMed Citation Articles by Sheng, H. Articles by Dlugosz, A. A.

Dissecting the Oncogenic Potential of Gli2

Deletion of an NH₂-Terminal Fragment Alters Skin Tumor Phenotype¹

Comprehensive Cancer Center and Departments of Dermatology [H. Sh., S. G., A. W., M. G., L. L., A. A. D.] and Pathology [L. L.], University of Michigan, Ann Arbor, Michigan 48109; Program in Developmental Biology, Hospital for Sick Children, and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada [R. M., C-c. H.]; Department of Molecular Oncology, Genentech, South San Francisco, California 94080 [K. L., F. J. d. S.]; and Laboratory of Developmental Biology, Institute for Molecular and Cellular Biology, Osaka University, Osaka 569-0871, Japan [H. Sa.]

Development of basal cell carcinomas (BCCs) in skin is associated with uncontrolled Sonic hedgehog (Shh) signaling, which operates primarily through the Gli family of transcription factors. Gli2 is a mediator of physiological Shh signaling in skin and is sufficient to produce BCCs when overexpressed by use of a Keratin 5 (K5) promoter. Analysis of Gli protein deletion mutants has identified an NH₂-terminal transcription repressor domain in Gli2 but not Gli1. To assess the potential involvement of the Gli2 repressor domain in skin tumor development, we overexpressed the Gli2N2 mutant in transgenic mice by use of the K5 promoter. K5-Gli2N2 mice developed a variety of skin tumors resembling human trichoblastomas, cylindromas, basaloid follicular hamartomas, and rarely, BCCs. In striking contrast, K5-Gli2 mice overexpressing wild-type Gli2 developed only BCCs. Other differences between tumors arising in these two sets of transgenic mice included their gross appearance, growth rate, and predilection for specific body sites. However, the expression levels of Shh target genes, which reflect the magnitude of Shh pathway activation, were not dramatically different. Tumors from K5-Gli2N2 mice, unlike human or mouse BCCs, gave rise to cell lines that constitutively expressed Shh target genes in vitro and were tumorigenic in nude mice. Interestingly, the phenotype of K5-Gli2N2 mice was strikingly similar to that reported after K5 promoter-driven overexpression of GLI1, which lacks an NH₂-terminal region homologous to the Gli2 repressor domain. These results underscore the qualitative difference in oncogenicity of GLI1 and Gli2 when overexpressed in skin, and reveal a previously unanticipated role for the Gli2 NH₂ terminus in defining tumor phenotype.

This article has been cited by other articles:

				M. Dentice, C. Luongo, S. Huang, R. Ambrosio, A. Elefante, D. Mirebeau-Prunier, A. M. Zavacki, G. Fenzi, M. Grachtchouk, M. Hutchin, et al. Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes PNAS, September 4, 2007; 104(36): 14466 - 14471. [Abstract] [Full Text] [PDF]

				M. Lauth, A. Bergstrom, T. Shimokawa, and R. Toftgard Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists PNAS, May 15, 2007; 104(20): 8455 - 8460. [Abstract] [Full Text] [PDF]

				N. J. Rowbotham, A. L. Hager-Theodorides, M. Cebecauer, D. K. Shah, E. Drakopoulou, J. Dyson, S. V. Outram, and T. Crompton Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation Blood, May 1, 2007; 109(9): 3757 - 3766. [Abstract] [Full Text] [PDF]

				S. J. Hatsell and P. Cowin Gli3-mediated repression of Hedgehog targets is required for normal mammary development Development, September 15, 2006; 133(18): 3661 - 3670. [Abstract] [Full Text] [PDF]

				M. Mancuso, S. Leonardi, M. Tanori, E. Pasquali, M. Pierdomenico, S. Rebessi, V. Di Majo, V. Covelli, S. Pazzaglia, and A. Saran Hair Cycle-Dependent Basal Cell Carcinoma Tumorigenesis in Ptc1neo67/+ Mice Exposed to Radiation. Cancer Res., July 1, 2006; 66(13): 6606 - 6614. [Abstract] [Full Text] [PDF]

				M. E. Hutchin, M. S.T. Kariapper, M. Grachtchouk, A. Wang, L. Wei, D. Cummings, J. Liu, L. E. Michael, A. Glick, and A. A. Dlugosz Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle Genes & Dev., January 15, 2005; 19(2): 214 - 223. [Abstract] [Full Text] [PDF]

				G. Regl, M. Kasper, H. Schnidar, T. Eichberger, G. W. Neill, M. P. Philpott, H. Esterbauer, C. Hauser-Kronberger, A.-M. Frischauf, and F. Aberger Activation of the BCL2 Promoter in Response to Hedgehog/GLI Signal Transduction Is Predominantly Mediated by GLI2 Cancer Res., November 1, 2004; 64(21): 7724 - 7731. [Abstract] [Full Text] [PDF]

				A. Brancaccio, A. Minichiello, M. Grachtchouk, D. Antonini, H. Sheng, R. Parlato, N. Dathan, A. A. Dlugosz, and C. Missero Requirement of the forkhead gene Foxe1, a target of sonic hedgehog signaling, in hair follicle morphogenesis Hum. Mol. Genet., November 1, 2004; 13(21): 2595 - 2606. [Abstract] [Full Text] [PDF]

				C. Adolphe, M. Narang, T. Ellis, C. Wicking, P. Kaur, and B. Wainwright An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis Development, October 15, 2004; 131(20): 5009 - 5019. [Abstract] [Full Text] [PDF]

				B. Ganss and A. Jheon ZINC FINGER TRANSCRIPTION FACTORS IN SKELETAL DEVELOPMENT Critical Reviews in Oral Biology & Medicine, September 1, 2004; 15(5): 282 - 297. [Abstract] [Full Text] [PDF]