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Downregulation of the upstream binding factor1 by glycogen synthase kinase3β in myeloid cells induced to differentiate
Author(s) -
Liu Mingli,
Tu Xiao,
FerrariAmorotti Giovanna,
Calabretta Bruno,
Baserga Renato
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21103
Subject(s) - downregulation and upregulation , gsk 3 , microbiology and biotechnology , proteasome , biology , lactacystin , phosphorylation , myeloid , gsk3b , proteasome inhibitor , cancer research , biochemistry , gene
The upstream binding factor 1 (UBF1), one of theproteins that regulate the activity of RNA polymerase I, is downregulated in 32D myeloid cells induced to differentiate into granulocytes, either by the type 1 insulin‐like growth factor (IGF‐1) or the granulocytic colony stimulating factor (G‐CSF). Downregulation of UBF1 is largely due to protein degradation, while mRNA levels are not affected. Inhibition of UBF1 degradation by lithium chloride (LiCl)and lactacystin suggest a role of glycogen synthase kinase β (GSK3β) in a proteasome‐dependent degradation of UBF. GSK3β phosphorylates in vitro and in vivo the UBF protein, which has five putative motifs for phosphorylation by GSK3β. Elimination and/or mutations of these motifs stabilize the UBF1 protein even in cells induced to differentiate. Conversely, a stably transfected, constitutively active GSK3β accelerates the downregulation of UBF1. We show further that activation of the differentiating protein C/EPBα in 32D cells transformed by the oncogenic BCR/ABL protein causes downregulation of UBF1. Finally, inhibition of differentiation of myeloid cells by a dominant negative mutant of Stat3 stabilizes the UBF1 protein, while rapamycin‐induced differentiation of myeloid cells downregulates UBF1 levels. Taken together, our results indicate that the induction of granulocytic differentiation in 32D murine myeloid cells causes the degradation of UBF1, via GSK3β and the proteasome pathway. J. Cell. Biochem. 100: 1154–1169, 2007. © 2006 Wiley‐Liss, Inc.