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 Regl, G. Articles by Aberger, F. Search for Related Content PubMed PubMed Citation Articles by Regl, G. Articles by Aberger, F.

Activation of the BCL2 Promoter in Response to Hedgehog/GLI Signal Transduction Is Predominantly Mediated by GLI2

¹ Department of Molecular Biology, Division of Genomics, University of Salzburg, Salzburg, Austria; ² Medical University Vienna, Institute of Medical and Chemical Laboratory Diagnostics, Vienna, Austria; ³ Department of Pathology, St. Johann’s Hospital, Paracelsus Medical School, Salzburg, Austria; and ⁴ Center for Cutaneous Research, Barts and The London Queen Mary’s School of Medicine & Dentistry, University of London, United Kingdom

Aberrant activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of basal cell carcinoma (BCC). The zinc finger transcription factors GLI1 and GLI2 are considered mediators of the HH signal in epidermal cells, although their tumorigenic nature and their relative contribution to tumorigenesis are only poorly understood. To shed light on the respective role of these transcription factors in epidermal neoplasia, we screened for genes preferentially regulated either by GLI1 or GLI2 in human epidermal cells. We show here that expression of the key antiapoptotic factor BCL2 is predominantly activated by GLI2 compared with GLI1. Detailed promoter analysis and gel shift assays identified three GLI binding sites in the human BCL2 cis-regulatory region. We found that one of these binding sites is critical for conferring GLI2-specific activation of the human BCL2 promoter and that the selective induction of BCL2 expression depends on the zinc finger DNA binding domain of GLI2. In vivo, GLI2 and BCL2 were coexpressed in the outer root sheath of hair follicles and BCC and in plasma cells that infiltrated BCC tumor islands. On the basis of the latter observation, we analyzed plasma cell-derived tumors and found strong expression of GLI2 and BCL2 in neoplastic cells of plasmacytoma patients, implicating HH/GLI signaling in the development of plasma cell-derived malignancies. The results reveal a central role for GLI2 in activating the prosurvival factor BCL2, which may represent an important mechanism in the development or maintenance of cancers associated with inappropriate HH signaling.

This article has been cited by other articles:

				M. Kasper, V. Jaks, M. Fiaschi, and R. Toftgard Hedgehog signalling in breast cancer Carcinogenesis, June 1, 2009; 30(6): 903 - 911. [Abstract] [Full Text] [PDF]

				M. Yu, J. Gipp, J. W. Yoon, P. Iannaccone, D. Walterhouse, and W. Bushman Sonic Hedgehog-responsive Genes in the Fetal Prostate J. Biol. Chem., February 27, 2009; 284(9): 5620 - 5629. [Abstract] [Full Text] [PDF]

				G. V. Hegde, K. J. Peterson, K. Emanuel, A. K. Mittal, A. D. Joshi, J. D. Dickinson, G. J. Kollessery, R. G. Bociek, P. Bierman, J. M. Vose, et al. Hedgehog-Induced Survival of B-Cell Chronic Lymphocytic Leukemia Cells in a Stromal Cell Microenvironment: A Potential New Therapeutic Target Mol. Cancer Res., December 1, 2008; 6(12): 1928 - 1936. [Abstract] [Full Text] [PDF]

				S. Narita, A. So, S. Ettinger, N. Hayashi, M. Muramaki, L. Fazli, Y. Kim, and M. E. Gleave GLI2 Knockdown Using an Antisense Oligonucleotide Induces Apoptosis and Chemosensitizes Cells to Paclitaxel in Androgen-Independent Prostate Cancer Clin. Cancer Res., September 15, 2008; 14(18): 5769 - 5777. [Abstract] [Full Text] [PDF]

				A. Varas, C. Hernandez-Lopez, J. Valencia, S. Mattavelli, V. G. Martinez, L. Hidalgo, C. Gutierrez-Frias, A. G. Zapata, R. Sacedon, and A. Vicente Survival and function of human thymic dendritic cells are dependent on autocrine Hedgehog signaling J. Leukoc. Biol., June 1, 2008; 83(6): 1476 - 1483. [Abstract] [Full Text] [PDF]

				G. V. Hegde, C. M. Munger, K. Emanuel, A. D. Joshi, T. C. Greiner, D. D. Weisenburger, J. M. Vose, and S. S. Joshi Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma Mol. Cancer Ther., June 1, 2008; 7(6): 1450 - 1460. [Abstract] [Full Text] [PDF]

				T. Eichberger, A. Kaser, C. Pixner, C. Schmid, S. Klingler, M. Winklmayr, C. Hauser-Kronberger, F. Aberger, and A.-M. Frischauf GLI2-specific Transcriptional Activation of the Bone Morphogenetic Protein/Activin Antagonist Follistatin in Human Epidermal Cells J. Biol. Chem., May 2, 2008; 283(18): 12426 - 12437. [Abstract] [Full Text] [PDF]

				Z. Ji, F. C. Mei, B. H. Johnson, E. B. Thompson, and X. Cheng Protein Kinase A, not Epac, Suppresses Hedgehog Activity and Regulates Glucocorticoid Sensitivity in Acute Lymphoblastic Leukemia Cells J. Biol. Chem., December 28, 2007; 282(52): 37370 - 37377. [Abstract] [Full Text] [PDF]

				S. Thiyagarajan, N. Bhatia, S. Reagan-Shaw, D. Cozma, A. Thomas-Tikhonenko, N. Ahmad, and V. S. Spiegelman Role of GLI2 Transcription Factor in Growth and Tumorigenicity of Prostate Cells Cancer Res., November 15, 2007; 67(22): 10642 - 10646. [Abstract] [Full Text] [PDF]

				Y. Kim, J. W. Yoon, X. Xiao, N. M. Dean, B. P. Monia, and E. G. Marcusson Selective Down-Regulation of Glioma-Associated Oncogene 2 Inhibits the Proliferation of Hepatocellular Carcinoma Cells Cancer Res., April 15, 2007; 67(8): 3583 - 3593. [Abstract] [Full Text] [PDF]

				E. E. Bar, A. Chaudhry, M. H. Farah, and C. G. Eberhart Hedgehog Signaling Promotes Medulloblastoma Survival via BclII Am. J. Pathol., January 1, 2007; 170(1): 347 - 355. [Abstract] [Full Text] [PDF]

				M. Kasper, H. Schnidar, G. W. Neill, M. Hanneder, S. Klingler, L. Blaas, C. Schmid, C. Hauser-Kronberger, G. Regl, M. P. Philpott, et al. Selective Modulation of Hedgehog/GLI Target Gene Expression by Epidermal Growth Factor Signaling in Human Keratinocytes. Mol. Cell. Biol., August 1, 2006; 26(16): 6283 - 6298. [Abstract] [Full Text] [PDF]

				N. Bhatia, S. Thiyagarajan, I. Elcheva, M. Saleem, A. Dlugosz, H. Mukhtar, and V. S. Spiegelman Gli2 Is Targeted for Ubiquitination and Degradation by beta-TrCP Ubiquitin Ligase J. Biol. Chem., July 14, 2006; 281(28): 19320 - 19326. [Abstract] [Full Text] [PDF]

				N. Wajapeyee, R. Britto, H. M. Ravishankar, and K. Somasundaram Apoptosis Induction by Activator Protein 2{alpha} Involves Transcriptional Repression of Bcl-2 J. Biol. Chem., June 16, 2006; 281(24): 16207 - 16219. [Abstract] [Full Text] [PDF]

				J. Cayuso, F. Ulloa, B. Cox, J. Briscoe, and E. Marti The Sonic hedgehog pathway independently controls the patterning, proliferation and survival of neuroepithelial cells by regulating Gli activity Development, February 1, 2006; 133(3): 517 - 528. [Abstract] [Full Text] [PDF]

				E. Roessler, A. N. Ermilov, D. K. Grange, A. Wang, M. Grachtchouk, A. A. Dlugosz, and M. Muenke A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2 Hum. Mol. Genet., August 1, 2005; 14(15): 2181 - 2188. [Abstract] [Full Text] [PDF]