P27(KIP1) - A KEY MEDIATOR OF RETINOIC ACID-INDUCED GROWTH ARREST IN THE SMS-KCNR HUMAN NEUROBLASTOMA CELL-LINE

Retinoic acid (RA) treatment of SMS-KCNR neuroblastoma (NB) cells lead s to G1 growth arrest and neuronal differentiation. To investigate the molecular mechanisms by which RA alters cell growth, we analysed the expression and activity of components of the cell cycle machinery afte r culture in RA. Within 2 days of RA treatment and prior to the arrest of NE cells in the G1 phase of the cell cycle, there is a complete do wnregulation of G1 cyclin/Cdk activities. Protein levels for the G1 cy clin/Cdks were essentially unchanged during this time although there w as a decrease in the steady-state levels of p67(N-Myc) and hyperphosph orylated Rb proteins. The Cdk inhibitors, p21(Cipl) and p27(Kip1) were constitutively expressed in KCNR while p15(INK4B) and p16(INK4A) were not detected. RA induced an increase in the expression of p27(Kip1) b ut not p21(Cip1). Furthermore, coincident with the decrease in kinase activity there was an increase in G1 cyclin/Cdk bound p27(Kip1). These results indicate that changes in the level of p27(Kip1) and its bindi ng to G1 cyclin/Cdks may play a key role in RA induced growth arrest o f NB cells.