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Molecular and Cellular Biology, July 1999, p. 4798-4805, Vol. 19, No. 7
Department of Molecular Biology, Lerner Research Institute,
The Cleveland Clinic Foundation, Cleveland, Ohio
44195,1 and Department of
Immunology, Berlex Biosciences, Richmond, California
948042
Received 16 November 1998/Returned for modification 11 January
1999/Accepted 5 April 1999
The work of Reddy et al. (S. A. Reddy, J. A. Huang, and
W. S. Liao, J. Biol. Chem. 272:29167-29173, 1997) reveals
that phosphatidylinositol 3-kinase (PI3K) plays a role in transducing a
signal from the occupied interleukin-1 (IL-1) receptor to nuclear
factor
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Copyright © 1999, American Society for Microbiology. All rights reserved.
Activation of Phosphatidylinositol 3-Kinase in Response to
Interleukin-1 Leads to Phosphorylation and Activation of the
NF-
B p65/RelA Subunit
B (NF-
B), but the underlying mechanism remains to be
determined. We have found that IL-1 stimulates interaction of the IL-1
receptor accessory protein with the p85 regulatory subunit of PI3K,
leading to the activation of the p110 catalytic subunit. Specific PI3K
inhibitors strongly inhibit both PI3K activation and NF-
B-dependent
gene expression but have no effect on the IL-1-stimulated degradation of I
B
, the nuclear translocation of NF-
B, or the ability of NF-
B to bind to DNA. In contrast, PI3K inhibitors block the
IL-1-stimulated phosphorylation of NF-
B itself, especially the
p65/RelA subunit. Furthermore, by using a fusion protein containing the
p65/RelA transactivation domain, we found that overexpression of the
p110 catalytic subunit of PI3K induces p65/RelA-mediated
transactivation and that the specific PI3K inhibitor LY294,002
represses this process. Additionally, the expression of a
constitutively activated form of either p110 or the PI3K-activated
protein kinase Akt also induces p65/RelA-mediated transactivation.
Therefore, IL-1 stimulates the PI3K-dependent phosphorylation and
transactivation of NF-
B, a process quite distinct from the
liberation of NF-
B from its cytoplasmic inhibitor I
B.
*
Corresponding author. Mailing address: Lerner Research
Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave.,
Cleveland, OH 44195. Phone: (216) 444-3900. Fax: (216) 444-3279. E-mail: starkg{at}cesmtp.ccf.org.
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