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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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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DOI: https://doi.org/10.1038/sj.onc.1208264
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