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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1415-1424
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The cJun N-terminal kinase (JNK) signaling pathway mediates
induction of urokinase-type plasminogen activator (uPA) by the
alkylating agent MNNG
Maribel Parra,
Frederic Lluís,
Francesc Miralles,
Carme Caelles, and
Pura Muñoz-Cánoves
From the Departament de Oncològia Molecular,
Institut de Recerca Oncològica (IRO), Barcelona, Spain; Facultat
de Farmacia, Universitat de Barcelona, Barcelona, Spain.
The monofunctional alkylating agent
N-methyl-N-nitro-N-nitrosoguanidine (MNNG) is
a widespread environmental carcinogen that causes DNA lesions, leading
to cell death. However, MNNG can also trigger a cell-protective
response by inducing the expression of DNA repair/transcription-related
genes. We demonstrate that the urokinase-type plasminogen activator
(uPA) gene product, a broad spectrum extracellular protease
to which no DNA repair function has been assigned, is transcriptionally
induced by MNNG in C2C12 and NIH3T3 cells. This induction required an
AP1-enhancer element located at  2.4 kilobase (kb), because it was
abrogated by deletion of this site. MNNG was found to induce the
activation of JNK/SAPK and p38 mitogen-activated protein kinases
(MAPKs). Accordingly, we attempted to assess the contribution of each
of these MNNG-inducible MAPKs to uPA gene induction by this
alkylating agent. Coexpression of dominant negative versions of kinases
of the JNK pathway, such as catalytically inactive forms of MEKK1,
MKK7, and JNKK, and of cytoplasmic JNK-inhibitor JIP-1, as well as
treatment of cells with curcumin (which blocks JNK activation by MNNG),
inhibited MNNG-induced uPA transcriptional activity. In
contrast, neither dominant negative MKK6 nor SB203580, which
specifically inhibit p38 MAP kinase activation, abrogated the
MNNG-induced effect. Taken together, our results show that the JNK
signaling pathway links external MNNG stimulation and
AP1-dependent uPA gene expression, providing the first
functional dissection of a transcription-coupled signal transduction
pathway for MNNG.
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