ECTOPIC EXPRESSION OF P27(KIP1) IN OLIGODENDROCYTE PROGENITOR CELLS RESULTS IN CELL-CYCLE GROWTH ARREST

Oligodendrocyte differentiation is a complex process believed to be co ntrolled by an intrinsic mechanism associated with cell-cycle arrest. Recently, the cell-cycle inhibitor protein p27(Kip1) has been proposed as a key element in causing growth arrest of oligodendrocyte precurso r cells. To investigate the effects of p27 upon oligodendrocyte cell d evelopment, we have introduced the p27 cDNA in oligodendrocyte progeni tor cells using an adenovirus vector. Progenitor cells normally expres s low levels of p27, After adenoviral infection and p27 overexpression , progenitor cells were able to undergo cell-cycle arrest, even in the presence of strong mitogens. The effects of p27 were shown to be dire ctly upon cyclin-dependent kinase-2 (CDK2), the protein kinase complex responsible for G1/S transition, as immunodepletion of oligodendrocyt e extracts of p27 protein resulted in the activation of CDK2 activity, However, cells that became growth arrested owing to infection with p2 7 adenovirus did not display conventional oligodendrocyte differentiat ion markers, such as O4 or O1, Taken together, these data provide mech anistic evidence indicating that p27 is primarily involved in oligoden droglial progenitor proliferation by inhibiting CDK2 activity and indu cing oligodendrocyte cell-cycle arrest. (C) 1998 John Wiley & Sons, In c.