Activation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway by Retinoic Acid Is Required for Neural Differentiation of SH-SY5Y Human Neuroblastoma Cells

• Published in: The Journal of biological chemistry Vol. 277; no. 28; pp. 25297 - 25304
• Main Authors: López-Carballo, Gracia, Moreno, Lucrecia, Masiá, Susana, Pérez, Paloma, Barettino, Domingo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2002; American Society for Biochemistry and Molecular Biology
• Subjects: Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation - drug effects; DNA-Binding Proteins - metabolism; Enzyme Activation; Humans; Molecular Sequence Data; Neuroblastoma - pathology; Phosphatidylinositol 3-Kinases - metabolism; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Signal Transduction - drug effects; Transcription Factors - metabolism; Tretinoin - pharmacology; Tumor Cells, Cultured
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M201869200

Retinoic acid (RA) induces neural differentiation of SH-SY5Y neuroblastoma cells. We show that the mRNA levels of the differentiation-inhibiting basic helix-loop-helix transcription factors ID1,ID2, and ID3 are down-regulated during RA-induced differentiation of SH-SY5Y cells. The levels of ID proteins decreased in parallel to the observed transcriptional repression. The expression of other basic helix-loop-helix genes changed during RA-induced differentiation: expression of neuroblast-specificASCL1 (HASH-1) gene was promptly reduced after RA treatment, whereas expression of differentiation-promoting genes NEUROD6 (NEX-1, HATH-2) andNEUROD1 was increased. Treatments with 12-O-tetradecanoylphorbol-13-acetate, another inducer of neuroblastoma cell differentiation, also resulted in coordinated down-regulation of ID gene expression, underscoring the role of ID genes in differentiation. Down-regulation ofID gene expression by RA involves a complex mechanism because full transcriptional repression required newly synthesized proteins and signaling by phosphatidylinositol 3-kinase (PI3K). RA treatment activates the PI3K/Akt signaling pathway, resulting in increased PI3K activity in extracts from RA-treated cells and a rapid increase in phosphorylation of Akt in Ser-473. Inhibition of PI3K by LY294002 impaired RA-induced differentiation, as assessed by morphological and biochemical criteria. We propose that RA, by activating the PI3K/Akt signaling pathway, plays an important role in the regulation of neuronal cell survival.