Cyclin D1-dependent regulation of B-myb activity in early stages of neuroblastoma differentiation.
Levels of the transcription factor B-myb must be down-regulated to allow terminal differentiation of neuroectodermal cells and yet its constitutive expression induces early markers of neural differentiation. Thus, we investigated potential mechanisms of enhanced B-myb activity in early stages of neural differentiation. We report here that B-myb expression does not decrease, cyclin A and Sp1 levels remain constant while p21 levels increase continuously upon retinoic acid-induced differentiation of the LAN-5 neuroblastoma cell line. In contrast, cyclin D1 expression is down-regulated at the onset of the differentiative process by protein destabilization. Luciferase assays of promoter activity indicate that B-myb-dependent transactivation is enhanced in LAN-5 cells treated with retinoic acid (RA) for 24 h. The enhancement is independent from cyclin A but is suppressed by a degradation-resistant mutant form of cyclin D1. The importance of cyclin D1 in controlling B-myb activity is further suggested by co-immunoprecipitation experiments, showing that the amount of cyclin D1 co-immunoprecipitated with B-myb decreased after RA treatment. Thus, B-myb may play an active role in the early stages of differentiation when its transactivation activity is enhanced as a consequence of cyclin D1 down-modulation.
Cesi
V
V
ENEA Research Center Casaccia, Biotechnology Unit, Section of Toxicology and Biomedical Sciences, Via Angullarese, 301, 00060 S Maria di Galeria Rome, Italy.
Tanno
B
B
Vitali
R
R
Mancini
C
C
Giuffrida
M L
ML
Calabretta
B
B
Raschellà
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D011268:Pregnancy-Specific beta 1-Glycoproteins / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D015415:Biomarkers; D018797:Cell Cycle Proteins; D019925:Cyclin A; D004268:DNA-Binding Proteins; C064352:MYBL2 protein, human; D011268:Pregnancy-Specific beta 1-Glycoproteins; D015534:Trans-Activators; D019938:Cyclin D1; D014212:Tretinoin; D020741:rho GTP-Binding Proteins