title: Accumulation of p27 KIP1 is associated with BMP2-induced growth arrest and neuronal differentiation of human neuroblastoma-derived cell lines.
abstract: Bone morphogenetic proteins (BMPs) play an essential role in cell fate determination. In this study, we found that BMP2 treatment resulted in growth arrest and differentiation in human neuroblastoma-derived cell lines, SH-SY5Y and RTBM1. Within 30min of BMP2 exposure, phosphorylation of Smad1/5 was observed in these cell lines. In RTBM1 cells, BMP2-induced differentiation was accompanied by a significant decrease in the expression level of DAN, an antagonist of BMP in frog embryos. Immunoblot analysis revealed that BMP2 treatment caused a down-regulation of p53 family members and hence of cyclin-dependent kinase inhibitor p21(WAF1). We found a significant accumulation of p27(KIP1) in response to BMP2, whereas the expression level of Skp2, which is required for ubiquitin-dependent p27(KIP1) degradation, was decreased during this differentiation process. Our results suggest that p27(KIP1) contributes to the BMP-induced growth arrest and neuronal differentiation of neuroblastoma, and BMP treatment might provide a new therapeutic strategy.
authors.affiliation: Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan. ynakamur@chiba-cc.jp
authors.forename: Yohko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Sakiyama
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002675:Child, Preschool; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D007223:Infant; D009447:Neuroblastoma / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C490087:NBL1 protein, human; D011506:Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27