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J Biol Chem, Vol. 274, Issue 10, 6747-6753, March 5, 1999
From the Department of Veterans Affairs Palo Alto Health Care
System, Palo Alto, California 94304
Oncostatin M (OM) activates the transcription of
the human low density lipoprotein receptor (LDLR) in HepG2 cells
through a sterol-independent mechanism. Our previous studies showed
that mutations within the repeat 3 sequence of the LDLR promoter
significantly decreased OM activity on LDLR promoter luciferase
reporter constructs that contain the sterol responsive element-1
(repeat 2) and Sp1 binding sites (repeats 1 and 3). In this study, we
investigated the signal transduction pathways that are involved in
OM-induced LDLR transcription. In HepG2 cells, OM induced a rapid
increase in LDLR mRNA expression, with increases detected at 30 min
and maximal induction at 1 h. This OM effect was not blocked by
protein synthesis inhibitors, inhibitors of p38 kinase,
phosphatidylinositol 3-kinase, or c-Jun N-terminal kinase, but OM
activity was completely abolished by pretreating cells with inhibitors
of the extracellular signal-regulated kinase (ERK) kinase (mitogen/ERK
kinase (MEK)). To investigate whether the repeat 3 sequence of the LDLR
promoter is the OM-responsive element that converts ERK activation at
the promoter level, three luciferase reporters, pLDLR-TATA containing only the TATA-like elements of the promoter, pLDLR-R3 containing repeat
3 and the TATA-like elements, and pLDLR-234 containing repeats 1, 2, 3 and the TATA-like elements were constructed and transiently transfected
into HepG2 cells. OM had no effect on the basal promoter construct
pLDLR-TATA; however, including a single copy of repeat 3 sequence in
the TATA vector (pLDLR-R3) resulted in a full OM response. The activity
of OM on pLDLR-R3 was identical to that of pLDLR-234. Importantly, the
ability of OM to increase luciferase activities in both pLDLR-R3- and
pLDLR-234-transfected cells was blocked in a dose-dependent
manner by inhibition of MEK. These results demonstrate that the
mitogen-activated protein kinase MEK/ERK cascade is the essential
signaling pathway by which OM activates LDLR gene transcription and
provide the first evidence that the repeat 3 element is a new
downstream target of ERK activation.
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