The association of GSK3 beta with E2F1 facilitates nerve growth factor-induced neural cell differentiation.
It is widely acknowledged that E2F1 and GSK3beta are both involved in the process of cell differentiation. However, the relationship between E2F1 and GSK3beta in cell differentiation has yet to be discovered. Here, we provide evidence that in the differentiation of PC12 cells induced by nerve growth factor (NGF), GSK3beta was increased at both the mRNA and protein levels, whereas E2F1 at these two levels was decreased. Both wild-type GSK3beta and its kinase-defective mutant GSK3beta KM can inhibit E2F1 by promoting its ubiquitination through physical interaction. In addition, the colocalization of GSK3beta and E2F1 and their subcellular distribution, regulated by NGF, were observed in the process of PC12 differentiation. At the tissue level, GSK3beta colocalized and interacted with E2F1 in mouse hippocampus. Furthermore, GSK3beta facilitated neurite outgrowth by rescuing the promoter activities of Cdk inhibitors p21 and p15 from the inhibition caused by E2F1. To summarize, our findings suggest that GSK3beta can promote the ubiquitination of E2F1 via physical interaction and thus inhibit its transcription activity in a kinase activity independent manner, which plays an important role in the NGF-induced PC12 differentiation.
Zhou
Fangfang
F
State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China.
Zhang
Long
L
Wang
Aijun
A
Song
Bo
B
Gong
Kai
K
Zhang
Lihai
L
Hu
Min
M
Zhang
Xiufang
X
Zhao
Nanming
N
Gong
Yandao
Y
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002522:Chlorocebus aethiops; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015533:Transcriptional Activation / Q000235:genetics; D054875:Ubiquitination
D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D020932:Nerve Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3