Primers on Molecular Pathways GLI: More Than Just Hedgehog?

Overview

Journal Pancreatology

Specialties Endocrinology
Gastroenterology

Date 2008 May 24

PMID 18497536

Citations 20

Authors

Martin E Fernandez-Zapico

Affiliations

Soon will be listed here.

Abstract

GLI proteins, highly conserved in vertebrates and invertebrates, are critical in modulating embryonic development and adult tissue homeostasis. These proteins are zinc-finger-containing transcription factors that were originally identified by genetic screening of embryonic lethal mutants of Drosophila melanogaster. Alterations in GLI activity can lead to tumor development in tissues of different origin including the pancreas. GLI activity is mainly regulated by the Hedgehog pathway, via a ligand-receptor complex that triggers a signaling cascade that activates GLI transcription factors, which in turn regulate gene expression, an essential step of Hedgehog-mediated cellular effects. Interestingly, recent reports show the ability of other signaling cascades to modulate GLI function in cancer cells including RAS and TGF-beta, two pathways implicated in pancreatic carcinogenesis. Thus, these findings suggest that GLI proteins are not an exclusive downstream target of Hedgehog but rather a common effector of a network of signaling pathways controlling pancreatic carcinogenesis. and IAP.

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References

Ruiz i Altaba A, Sanchez P, Dahmane N . Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002; 2(5):361-72. DOI: 10.1038/nrc796. View

Riobo N, Manning D . Pathways of signal transduction employed by vertebrate Hedgehogs. Biochem J. 2007; 403(3):369-79. DOI: 10.1042/BJ20061723. View

Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E . Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell. 2006; 124(1):47-59. DOI: 10.1016/j.cell.2005.10.042. View

Pasca di Magliano M, Hebrok M . Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2004; 3(12):903-11. DOI: 10.1038/nrc1229. View

Morton J, Mongeau M, Klimstra D, Morris J, Lee Y, Kawaguchi Y . Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007; 104(12):5103-8. PMC: 1828712. DOI: 10.1073/pnas.0701158104. View

Lauth M, Toftgard R . Non-canonical activation of GLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle. 2007; 6(20):2458-63. DOI: 10.4161/cc.6.20.4808. View

Bigelow R, Chari N, Unden A, Spurgers K, Lee S, Roop D . Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem. 2003; 279(2):1197-205. DOI: 10.1074/jbc.M310589200. View

Regl G, Kasper M, Schnidar H, Eichberger T, Neill G, Philpott M . Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 2004; 64(21):7724-31. DOI: 10.1158/0008-5472.CAN-04-1085. View

Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz A, Hebrok M . Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 2006; 20(22):3161-73. PMC: 1635150. DOI: 10.1101/gad.1470806. View

10.

Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S . Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem. 1999; 274(12):8143-52. DOI: 10.1074/jbc.274.12.8143. View

11.

Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, Ten Dijke P . Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 2007; 67(14):6981-6. DOI: 10.1158/0008-5472.CAN-07-0491. View

12.

Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V . Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A. 2007; 104(14):5895-900. PMC: 1838820. DOI: 10.1073/pnas.0700776104. View

13.

Ji Z, Mei F, Xie J, Cheng X . Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem. 2007; 282(19):14048-55. DOI: 10.1074/jbc.M611089200. View

14.

Kasper M, Regl G, Frischauf A, Aberger F . GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur J Cancer. 2006; 42(4):437-45. DOI: 10.1016/j.ejca.2005.08.039. View

15.

Thayer S, Pasca di Magliano M, Heiser P, Nielsen C, Roberts D, Lauwers G . Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003; 425(6960):851-6. PMC: 3688051. DOI: 10.1038/nature02009. View

16.

Dai P, Shinagawa T, Nomura T, Harada J, Kaul S, Wadhwa R . Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes Dev. 2002; 16(22):2843-8. PMC: 187484. DOI: 10.1101/gad.1017302. View

17.

Ruiz i Altaba A, Mas C, Stecca B . The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol. 2007; 17(9):438-47. PMC: 2601665. DOI: 10.1016/j.tcb.2007.06.007. View

18.

Cheng S, Bishop J . Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci U S A. 2002; 99(8):5442-7. PMC: 122788. DOI: 10.1073/pnas.082096999. View