Ectopic expression of p27Kip1 in oligodendrocyte progenitor cells results in cell-cycle growth arrest.
Oligodendrocyte differentiation is a complex process believed to be controlled 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 precursor cells. To investigate the effects of p27 upon oligodendrocyte cell development, we have introduced the p27 cDNA in oligodendrocyte progenitor cells using an adenovirus vector. Progenitor cells normally express 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 directly upon cyclin-dependent kinase-2 (CDK2), the protein kinase complex responsible for G1/S transition, as immunodepletion of oligodendrocyte extracts of p27 protein resulted in the activation of CDK2 activity. However, cells that became growth arrested owing to infection with p27 adenovirus did not display conventional oligodendrocyte differentiation markers, such as O4 or O1. Taken together, these data provide mechanistic evidence indicating that p27 is primarily involved in oligodendroglial progenitor proliferation by inhibiting CDK2 activity and inducing oligodendrocyte cell-cycle arrest.
Tikoo
R
R
Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10012, USA.
Osterhout
D J
DJ
Casaccia-Bonnefil
P
P
Seth
P
P
Koff
A
A
Chao
M V
MV
D000256:Adenoviridae / Q000235:genetics; D000963:Antimetabolites; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006801:Humans; D007150:Immunohistochemistry; D009836:Oligodendroglia / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics*
D000963:Antimetabolites; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; C102333:histone H1 kinase; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D001973:Bromodeoxyuridine