AP-1/C-jun and C-myc Regulation During Megakaryocytic Differentiation of a Human Bi-potential Growth-factor-dependent Cell Line
作者:
DerigsH. G.,
MorganD. A.,
HoffmanR.,
LitzS. L.,
SrourE. F.,
BrandtJ. E.,
BoswellH. S.,
期刊:
Platelets
(Taylor Available online 1995)
卷期:
Volume 6,
issue 1
页码: 24-30
ISSN:0953-7104
年代: 1995
DOI:10.3109/09537109509013258
出版商: Taylor&Francis
数据来源: Taylor
摘要:
Terminal megakaryocytic development is characterized by nuclear poly ploidization, appearance of specific granules, and enhanced expression of membrane platelet glycoproteins. We utilized a human GM-CSF-dependent cell line, MB-02, which is capable of under going megakaryocytic differentiation, to examine the molecular events underlying this process. The responses of MB-02 to the protein kinase C (PKC) agonist, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were examined. GM-CSF dependent proliferation of MB-02, as measured by3H-thymidine uptake, was greater than 95% inhibited by TPA (16 nM), but was not affected by the inactive stereoisomer, 4-α-phorbol-12,13-didecanoate (4-αPDD). Transient exposure of cells to GM-CSF after growth factor deprivation led to rapid, high-level expression of normal-sized c-myc mRN A transcripts above baseline. C-myc expression was turned off by TPA (16 nM) stimulation of cells within 2-4 h. This TPA-mediated effect likely occurred at the transcriptional level since the half life of c-myc mRN A induced by GM-CSF was less than 30 min. Treatment of cells with TPA was associated with induction of c-jun and junB mRN A within 1-4 h. The protein products of these transcription factors are known to be part of the transcription factor complex Activator protein 1 (AP-1). Indeed, our data prove a rapid induction of AP-1 protein after TPA stimulation, as shown by mobility shift assays. In addition, TPA treatment resulted in expression of platelet surface glycoprotein IIb/IIIa complex (gpIIb/IIIa). These studies suggest a link between PKC stimulation by TPA and AP-1 activation with downregulation of c-myc transcription on a molecular level. At the cellular level, PKC activation was related to the acquisition of several features of the megakaryocyte development programme associated with the switch from cell proliferation to maturation.
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