Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1

Bradley S Dixon; David Evanoff; Wei B Fang; Michael J Dennis

doi:10.1152/ajpcell.00289.2001

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Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1

Journal article

Peer reviewed

Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1

Bradley S Dixon, David Evanoff, Wei B Fang and Michael J Dennis

American Journal of Physiology: Cell Physiology, Vol.283(1), pp.C193-203

07/2002

DOI: 10.1152/ajpcell.00289.2001

PMID: 12055088

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Abstract

The mechanism by which the bradykinin B1 receptor (B1R) inhibits platelet-derived growth factor (PDGF)-stimulated proliferation was investigated in cultured rat mesenteric arterial smooth muscle cells. The B1R agonist des-Arg9-bradykinin (DABK) was found to inhibit PDGF-mediated activation of the cyclin E-cyclin-dependent kinase 2 (Cdk2) complex and to prevent hyperphosphorylation of retinoblastoma protein. DABK did not inhibit upregulation of cyclin E expression but increased expression of the Cdk2 inhibitor p27Kip1 and the association of p27Kip1 with the cyclin E-Cdk2 complex. In addition, DABK inhibited the PDGF-stimulated expression of cyclin D that would otherwise siphon p27Kip1 away from inhibition of cyclin E-Cdk2. The signaling mechanism by which DABK regulated p27Kip1 was explored. DABK was found to stimulate the activity of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) and to prolong activation of MEK and ERK by PDGF. Inhibition of ERK activation with the MEK inhibitors PD-98059 and U-0126 as well as the Src family kinase inhibitor PP2 completely blocked the effect of DABK to increase p27Kip1 and partially reversed the DABK-mediated inhibition of PDGF-stimulated proliferation. These studies demonstrate that the B1R inhibits PDGF-stimulated mitogenesis in part by prolonged activation of ERK leading to increased expression of p27Kip1.

Bradykinin - analogs & derivatives

Cyclin-Dependent Kinases - metabolism

Male

Mitogen-Activated Protein Kinase Kinases - metabolism

Cyclin-Dependent Kinase 2

Time Factors

Receptor, Bradykinin B1

Protein-Serine-Threonine Kinases - antagonists & inhibitors

Cyclin-Dependent Kinases - antagonists & inhibitors

Bradykinin - pharmacology

Protein-Serine-Threonine Kinases - metabolism

Tumor Suppressor Proteins - metabolism

CDC2-CDC28 Kinases

Receptors, Bradykinin - physiology

Cyclin A - metabolism

src-Family Kinases - antagonists & inhibitors

Cell Cycle Proteins - metabolism

Cells, Cultured

Enzyme Inhibitors - pharmacology

Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors

Rats

Platelet-Derived Growth Factor - pharmacology

Rats, Sprague-Dawley

Cyclin-Dependent Kinase Inhibitor p27

G1 Phase

Animals

Mitosis - physiology

Cyclin E - metabolism

Enzyme Activation - physiology

Mitogen-Activated Protein Kinases - metabolism

Details

Title: Subtitle: Bradykinin B1 receptor blocks PDGF-induced mitogenesis by prolonging ERK activation and increasing p27Kip1
Creators: Bradley S Dixon - Division of Nephrology, Department of Medicine, Department of Veterans Affairs Medical Center and University of Iowa College of Medicine, Iowa City, Iowa 52242-1081, USA. bradley-dixon@uiowa.edu
David Evanoff
Wei B Fang
Michael J Dennis
Resource Type: Journal article
Publication Details: American Journal of Physiology: Cell Physiology, Vol.283(1), pp.C193-203
DOI: 10.1152/ajpcell.00289.2001
PMID: 12055088
ISSN: 0363-6143
eISSN: 1522-1563
Grant note: DK-25295 / NIDDK NIH HHS
Language: English
Date published: 07/2002
Academic Unit: Nephrology; Internal Medicine
Record Identifier: 9984094716402771

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