Posttranscriptional regulation of p18 and p27 Cdk inhibitor proteins and the timing of oligodendrocyte differentiation.
A cell-intrinsic timer helps control when rodent oligodendrocyte precursor cells (OPCs) exit the cell cycle and terminally differentiate when cultured in platelet-derived growth factor (PDGF) and thyroid hormone (TH). There is evidence that the cyclin-dependent kinase inhibitor (CKI) p27/Kip1 (p27) is a component of this TH-regulated timer, as it increases as OPCs proliferate and is required for the timer to operate accurately. Here, we provide evidence that another CKI, p18/INK (p18), may also be a component of the timer: it increases as OPCs proliferate, and its overexpression in OPCs accelerates the timer, causing the cells to differentiate prematurely. We also show that the overexpression of p27 accelerates the timer and that the increases in both p27 and p18 that occur in proliferating OPCs are controlled posttranscriptionally. By contrast, we show that the overexpression of either p18 or p27 in OPCs proliferating in PDGF and the absence of TH greatly slows the cell cycle but fails to accelerate the spontaneous differentiation that normally occurs independently of TH.
Tokumoto
Yasuhito M
YM
Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.
Apperly
James A
JA
Gao
Fen-Biao
FB
Raff
Martin C
MC
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers; D004791:Enzyme Inhibitors; D005455:Fluorescent Antibody Technique; D009836:Oligodendroglia / Q000166:cytology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013963:Thyroid Hormones / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
C493962:Cdkn1b protein, rat; C493973:Cdkn2c protein, rat; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D017931:DNA Primers; D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D013963:Thyroid Hormones; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003513:Cycloheximide