Phorbol esters inhibit the Hedgehog signalling pathway downstream of Suppressor of Fused, but upstream of Gli

• Published in: Oncogene Vol. 26; no. 35; pp. 5163 - 5168
• Main Authors: Lauth, M, Bergström, Å, Toftgård, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.08.2007; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Apoptosis; Biochemistry; Biological and medical sciences; Cancer; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Cilia; Esters; Fundamental and applied biological sciences. Psychology; Hedgehog protein; Hedgehog Proteins - antagonists & inhibitors; Human Genetics; Inhibitor drugs; Internal Medicine; Kinases; MAP kinase; MAP Kinase Kinase 1 - metabolism; Medicine; Medicine & Public Health; Mice; Molecular and cellular biology; NIH 3T3 Cells; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncology; Pharmacology; Phorbol esters; Phorbol Esters - pharmacology; Physiological aspects; Protein kinase; Protein kinase C; Protein Kinase C-delta - metabolism; Protein kinases; Proteins; Repressor Proteins - genetics; Repressor Proteins - metabolism; short-communication; Signal transduction; Signal Transduction - drug effects; Tetradecanoylphorbol Acetate - pharmacology; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription factors; Tumors; Zinc Finger Protein GLI1; Hedgehog signalling; phorbol ester; protein kinase C; Signal transduction; Protein kinase C; Enzyme; Transferases; Inhibition; Carcinogenesis; Cell signaling
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210321

The developmentally important Hedgehog (Hh) signal transduction pathway, which has recently been implicated in several forms of cancer, is subject to regulation by several protein kinases. Here, we address the role of protein kinase C δ in pathway inhibition and show that cellular depletion or pharmacological inhibition of this kinase isoform results in a blockade of signalling between Suppressor of Fused and the Gli transcription factors. We further provide evidence that the observed pathway inhibition is independent of primary cilia and the mitogen-activated protein kinase kinase (Mek1) kinase. These findings allowed for the rapid dissection of downstream Hh pathway activation mechanisms in human tumour cells and demonstrate a surprising variation in how cells can activate signalling in a ligand- and receptor-independent manner.