Regulation of cyclin D1 expression by autocrine IGF-I in human BON neuroendocrine tumour cells.
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 (NFkappaB) 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/NFkappaB/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.
von Wichert
Götz
G
Department of Internal Medicine I, University of Ulm, D-89081 Ulm, Germany.
Haeussler
Ulla
U
Greten
Florian R
FR
Kliche
Stefanie
S
Dralle
Henning
H
Böhm
Bernhard O
BO
Adler
Guido
G
Seufferlein
Thomas
T
D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000502:physiology; D020703:ras GTPase-Activating Proteins / Q000502:physiology
D002867:Chromones; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D020744:rac GTP-Binding Proteins; D020703:ras GTPase-Activating Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human