B-MYB is hypophosphorylated and resistant to degradation in neuroblastoma: implications for cell survival.
B-MYB is an oncoprotein highly expressed and frequently amplified in human neoplasia. B-MYB is more expressed in neuroblastoma patients with adverse prognostic indicators, corroborating the hypothesis that it plays an important role in this pediatric malignancy. While attempting targeting strategies for therapeutic purposes, we found that the B-MYB protein was difficult to downregulate in neuroblastoma cells using siRNA approaches. This lead us to discover that the B-MYB protein half-life is increased in neuroblastoma compared to other normal or transformed human cell lines. The B-MYB protein is quickly destroyed and apoptosis is induced in Ewing sarcoma cells exposed to UV irradiation. In contrast, neuroblastoma cells are resistant to UV-induced apoptosis and B-MYB protein levels do not change in UV-treated cells. In further experiments, we show that the B-MYB protein extracted from neuroblastoma cells is hypophosphorylated. It was previously shown that B-MYB phosphorylation activates its transcriptional activity but also promotes its destruction. Overexpression of a non-phosphorylatable B-MYB mutant protects cells from UV-induced apoptosis, suggesting that its reduced phosphorylation, rather than causing its inactivation, facilitates B-MYB pro-survival activity. Thus, expression of stable, hypophosphorylated B-MYB in neuroblastoma may promote cell survival and induce aggressive tumour growth.
Schwab
Rebekka
R
Molecular Haematology and Cancer Biology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Caccamo
Alessandro
A
Bettuzzi
Saverio
S
Anderson
John
J
Sala
Arturo
A
D017209:Apoptosis / Q000502:physiology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C064352:MYBL2 protein, human; D015534:Trans-Activators