Nitric Oxide-stimulated Guanine Nucleotide Exchange on p21
(*)
- Harry M. Lander(1)(§),
- Jason S. Ogiste(1),
- S. Frieda A. Pearce(2),
- Roberto Levi(1) and
- Abraham Novogrodsky(3)(4)
- From the (1)Department of Pharmacology and
- (2)Medicine, Division of Hematology/Oncology, Cornell University Medical College, New York, New York 10021, the
- (3)Felsenstein Medical Research Center, Beilinson Campus, Petah-Tikva 49100, Israel, and the
- (4)Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
- § To whom correspondence should be addressed: Dept. of Biochemistry, Cornell University Medical College, New York, NY 10021. Tel.: 212-746-6462; Fax: 212-746-8789.
Abstract
The protooncogene p21
, a monomeric G protein family member, plays a critical role in converting extracellular signals into intracellular biochemical
events. Here, we report that nitric oxide (NO) activates p21
in human T cells as evidenced by an increase in GTP-bound p21
. In vitro studies using pure recombinant p21
demonstrate that the activation is direct and reversible. Circular dichroism analysis reveals that NO induces a profound
conformational change in p21
in association with GDP/GTP exchange. The mechanism of activation is due to S-nitrosylation of a critical cysteine residue which stimulates guanine nucleotide exchange. Furthermore, we demonstrate that
p21
is essential for NO-induced downstream signaling, such as NF-κB activation, and that endogenous NO can activate p21
in the same cell. These studies identify p21
as a target of NO in T cells and suggest that NO activates p21
by an action which mimics that of guanine nucleotide exchange factors.
Footnotes
-
↵* This work was supported by United States Public Health Service Grants HL34215, HL46403, and HL07423. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- NO
-
nitric oxide
- HUVEC
-
human umbilical vein endothelial cells
- GEF
-
guanine nucleotide exchange factors.
-
- Received December 30, 1994.
- Revision received February 1, 1995.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
