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PMID: 11252720 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

p21cip1 is required for the differentiation of oligodendrocytes independently of cell cycle withdrawal.

EMBO reports ·Vol. 2 ·No. 1 ·2001-01-00 ·Pages 27-34

Zezula J, Casaccia-Bonnefil P, Ezhevsky SA, Osterhout DJ, Levine JM, Dowdy SF, Chao MV, Koff A

Abstract

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.

MeSH Terms
Animals Animals, Newborn Antimetabolites/pharmacology Brain/metabolism Bromodeoxyuridine/pharmacology Cell Cycle/drug effects Cell Cycle Proteins Cell Differentiation/drug effects Cell Division Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16/metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinase Inhibitor p27 Cyclins/metabolism,physiology Enzyme Inhibitors/pharmacology Flavonoids/pharmacology Genotype Immunohistochemistry Kinetics MAP Kinase Kinase 1 Mice Microtubule-Associated Proteins/metabolism Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors Oligodendroglia/metabolism Protein Serine-Threonine Kinases/antagonists & inhibitors Time Factors Transduction, Genetic Tumor Suppressor Proteins
Chemicals
Antimetabolites Cdkn1a protein, mouse Cdkn1b protein, mouse Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinase Inhibitor p21 Cyclins Enzyme Inhibitors Flavonoids Microtubule-Associated Proteins Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27 Protein Serine-Threonine Kinases MAP Kinase Kinase 1 Map2k1 protein, mouse Mitogen-Activated Protein Kinase Kinases Bromodeoxyuridine 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Zezula J
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Casaccia-Bonnefil P
Ezhevsky S A
Osterhout D J
Levine J M
Dowdy S F
Chao M V
Koff A
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Article Info
Journal
EMBO reports
Abbr.
EMBO Rep
ISSN
1469-221X
DOI
10.1093/embo-reports/kve008
Published
2001-01-00
Pages
27-34
Language
English
Region
England
NLM ID
100963049
PMCID
PMC1083805
Subset
IM
Grants
NCI NIH HHS · R01 CA089563 · United States
NCI NIH HHS · P30 CA008748 · United States
NIGMS NIH HHS · GM52597 · United States
NCI NIH HHS · CA08748 · United States
NIGMS NIH HHS · R01 GM052597 · United States
External Links
PubMed source DOI: 10.1093/embo-reports/kve008 PMC Full Text View journal details
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