p21cip1 is required for the differentiation of oligodendrocytes independently of cell cycle withdrawal.
Differentiation of most cell types requires both establishment of G1 arrest and the induction of a program related to achieving quiescence. We have chosen to study the differentiation of oligodendrocyte cells to determine the role of p27 and p21 in this process. Here we report that both p27 and p21 are required for the appropriate differentiation of these cells. p27 is required for proper withdrawal from the cell cycle, p21 is not. Instead, p21 is required for the establishment of the differentiation program following growth arrest. Similar observations were made in vivo. We show that p21-/- cells withdraw from the cell cycle similar to wild-type cells; however, early in animal life, the brain is hypomyelinated, inferring that the loss of p21 delayed myelination in the cerebellum. We found that we could complement or bypass the differentiation failure in p21-/- cells with either PD98059, an inhibitor of Mek1, or by transducing them with a tat-p16ink4a protein. We concluded that the two cdk inhibitors serve non-redundant roles in this program of differentiation, with p27 being responsible for arrest and p21 having a function in differentiation independent of its ability to control exit from the cell cycle.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J
J
Zezula
P
P
Casaccia-Bonnefil
S A
SA
Ezhevsky
D J
DJ
Osterhout
J M
JM
Levine
S F
SF
Dowdy
M V
MV
Chao
A
A
Koff
D000818:Animals; D000831:Animals, Newborn; D000963:Antimetabolites / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005838:Genotype; D007150:Immunohistochemistry; D007700:Kinetics; D048369:MAP Kinase Kinase 1; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009836:Oligodendroglia / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins
D000963:Antimetabolites; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D001973:Bromodeoxyuridine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one