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Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells

Oncogene volume 24, pages 1284–1289 (2005)Cite this article

Abstract

Constitutive expression of cyclin D1 is a frequent abnormality in human cancer and sustains the transformed phenotype. We have previously demonstrated that cyclin D1 is constitutively expressed in human BON neuroendocrine tumour cells due to an autocrine insulin-like growth factor-I (IGF-I) loop. Here we examine the regulation of cyclin D1 expression by endogenously released IGF-I in BON cells. Cyclin D1 expression in these cells was found to be dependent on phosphatidylinositol 3-kinase (PI3-K), but independent of the extracellular signal-regulated kinase cascade. Ras- and Rac-GTPases were found to be upstream activators of cyclin D1 expression, whereas protein kinase B/AKT and nuclear factor kappa B (NFκB) could be established as downstream mediators of cyclin D1 transcription in response to endogenously released IGF-I in these cells. In addition, the Ras/PI3-K/AKT/Rac/NFκB/cyclin D1 signaling cascade triggered by endogenously released IGF-I is sufficient to sustain Rb phosphorylation and cdk4 kinase activity in BON cells. In conclusion, our data provide the first comprehensive map of the signaling events elicited by endogenously released IGF-I leading to constitutive cyclin D1 expression in human neuroendocrine tumour cells.

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Abbreviations

AKT:

protein kinase B

Cdk:

cyclin-dependent kinase

DNM:

Dulbeccos-F12 nut mix

ECL:

enhanced chemoluminescence

EMSA:

electrophoretic mobility shift assay

ERK:

extracellular signal-regulated kinase

FBS:

foetal bovine serum

IGF-I:

insulin-like growth factor-I

IGF-IN-Ab:

IGF-I immunoneutralizing antibody

IGF-IR:

insulin-like growth factor-I receptor

MEK:

mitogen-activated protein kinase kinase

NFκB:

nuclear factor kappa B

PI3-K:

phosphatidylinositol 3-kinase

Rb:

retinoblastoma protein

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Acknowledgements

We thank P Angel (DKFZ Heidelberg/Germany) for the ΔFos plasmid, J Downward (ICRF in London/UK), for the Ras-, Rac- and dnMEK plasmids and RM Schmid (Medical University of Ulm/Germany) for the AP-1- and cyclin D1 reporter plasmids.

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Authors and Affiliations

  1. Department of Internal Medicine I, University of Ulm, D-89081, Ulm, Germany

    Götz von Wichert, Florian R Greten, Bernhard O Böhm, Guido Adler & Thomas Seufferlein

  2. Department of Internal Medicine II, University of Ulm, D-89081, Ulm, Germany

    Ulla Haeussler & Stefanie Kliche

  3. Department of Surgery, Martin Luther University, D-06099, Halle, Germany

    Henning Dralle

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  1. Götz von Wichert
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  2. Ulla Haeussler
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Correspondence to Thomas Seufferlein.

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von Wichert, G., Haeussler, U., Greten, F. et al. Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells. Oncogene 24, 1284–1289 (2005). https://doi.org/10.1038/sj.onc.1208264

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