Effects of bone morphogenetic protein 2 on Id expression and neuroblastoma cell differentiation.
Bone morphogenetic proteins (BMPs) are secretory signal molecules that have a variety of regulatory functions during embryonic morphogenesis. BMP2 has been shown to induce differentiation in many cell types, mediated through the activation of its target genes: the inhibitors of differentiation (Id1-3) and key transcription factors. In this study, we investigated the effects of BMP2 on mouse neuroblastoma (Neuro2a) cell differentiation and regulation of the expression of Id1-3 and neural-specific transcription factors. Our results showed that BMP2 stimulation upregulated Id1-3 expression at the early stage of application by involvement of the Smad signaling pathway. BMP2 caused phosphorylation of Smad1/5/8 followed by upregulation of Id1-3. Co-incubation with Noggin, a BMP antagonist, or Smad1 siRNA transfection significantly inhibited phosphorylation of Smad1/5/8 and upregulation of Id protein. Furthermore, our results showed that BMP2-induced differentiation of Neuro2a cells into neurons by downregulating the expression of Id1-3 proteins and upregulating the expression of neural-specific transcriptional factors Dlx2, Brn3a, and NeuroD6. The results suggested that the transient upregulation of Id1-3 expression during the early phase of BMP stimulation may play a role in lineage specification and promote differentiation of neuroblastoma cells towards a neuronal phenotype. Subsequently, a coordinated increase in expression of proneural transcription factors and a decrease in Id1-3 expression may culminate in the transition from proliferation to neurogenesis and the terminal neuronal differentiation of neuroblastoma cells.
Du
Yang
Y
Department of Anatomy, The University of Hong Kong, SAR, China. duyang@hkusua.hku.hk
Yip
Henry
H
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D002454:Cell Differentiation; D015536:Down-Regulation; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D055396:Bone Morphogenetic Protein 2; D051796:Inhibitor of Differentiation Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors