Differentiation-associated expression and intracellular localization of cyclin-dependent kinase inhibitor p27KIP1 and c-Jun co-activator JAB1 in neuroblastoma.

Neuroblastoma is a unique pediatric cancer, which spontaneously regress in some infants and undergo maturation in older children. The cyclin-dependent kinase inhibitor p27KIP1 negatively control cell cycle progression and its expression is reported to be associated with differentiation and prognosis of some human cancers. To examine whether p27KIP1 is involved in differentiation of neuroblastomas, expression and localization of p27KIP1 in 30 cases of neuroblastic tumors were determined with immunohistochemistry. p27KIP1 was expressed in all cases, but staining intensity and intracellular localization varied in association with tumor differentiation. Primitive small round neuroblasts showed negative or only weak nuclear staining, while differentiating tumor cells displayed a novel, intense cytoplasmic positivity besides the nuclear staining, and mature ganglion cells showed intense positive reaction confined to the nucleus. A neuroblastoma cell line TGW was also immunostained positively for p27KIP1 in the cytoplasm after differentiation induction, and western blot analysis revealed an increase of p27KIP1 in these cells, corroborating the in vivo observations. JAB1, which is thought to bind p27KIP1 and transport it from the nucleus to the cytoplasm for proteasome/ubiquitin-mediated degradation, was found to be localized both in the cytoplasm and the nucleus in undifferentiated and differentiating tumors whereas located predominantly in the nucleus of differentiated tumor cells. These data indicate that the cytoplasmic localization of p27KIP1 in the process of differentiation is due to upregulation of p27KIP1 synthesis and subsequent degradation and suggest a role of p27KIP1 in differentiation of neuroblastoma.