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Research ArticleArticle

Tumor Suppressor p53 But Not cGMP Mediates NO-Induced Expression of p21 Waf1/Cip1/Sdi1 in Vascular Smooth Muscle Cells

Akio Ishida, Toshiyuki Sasaguri, Yoshikazu Miwa, Chiya Kosaka, Yoji Taba and Takeo Abumiya
Molecular Pharmacology November 1999, 56 (5) 938-946; DOI: https://doi.org/10.1124/mol.56.5.938
Akio Ishida
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Toshiyuki Sasaguri
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Yoshikazu Miwa
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Chiya Kosaka
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Yoji Taba
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Takeo Abumiya
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Abstract

Cyclin-dependent kinase inhibitor p21Waf1/Cip1/Sdi1 has been suggested to be involved in the antiproliferative effect of nitric oxide (NO) in vascular smooth muscle cells (VSMCs). To elucidate the mechanism underlying NO-induced p21 expression, we investigated the roles of tumor suppressor p53 and the guanylate cyclase-cGMP pathway. The induction of p21 by the NO donorS-nitroso-N-acetylpenicillamine (SNAP) seemed to be due to transactivation because SNAP elevated the activity of p21 promoter but did not stabilize p21 mRNA and protein. Because SNAP did not stimulate the deletion mutant of p21 promoter that lacked p53 binding sites, we tested the involvement of p53. The expression level of p53 was down-regulated after mitogenic stimulation, whereas it was sustained in the presence of SNAP. SNAP markedly stimulated DNA binding activity of p53. Furthermore, SNAP failed to induce p21 in VSMCs obtained from p53-knock out mice and in A431 cells that contained mutated p53. The antiproliferative effect of SNAP also was attenuated in these cells. NO stimulates guanylate cyclase and its product cGMP has been shown to inhibit VSMC proliferation. However, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, did not prevent SNAP-induced p21 expression. 8-Bromo-cGMP, 3-isobutyl-1-methylxanthine, and their combination did not induce p21. Although 8-bromo-cGMP had a small antiproliferative effect, the elevation of cGMP concentration induced by SNAP was little throughout the G1 phase. The antiproliferative effect of SNAP was not attenuated by Rp-8-bromoguanosine-3′,5′-monophosphorothioate, an inhibitor of cGMP-dependent protein kinase. These results suggested that NO induces p21 through a p53-dependent but cGMP-independent pathway.

Footnotes

    • Received April 8, 1999.
    • Accepted August 2, 1999.
  • Send reprint requests to: Toshiyuki Sasaguri, M.D., Ph.D., Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail: sasaguri{at}ri.ncvc.go.jp

  • This study was supported in part by grants from the Ministry of Health and Welfare [Research Grants for Cardiovascular Diseases (8A-1 and 9A-4), Science and Technology Agency (Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE)]; Japan Cardiovascular Research Foundation; Ichiro Kanehara Foundation; and Research Foundation for Cancer and Cardiovascular Diseases, Osaka, Japan.

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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Tumor Suppressor p53 But Not cGMP Mediates NO-Induced Expression of p21 Waf1/Cip1/Sdi1 in Vascular Smooth Muscle Cells

Akio Ishida, Toshiyuki Sasaguri, Yoshikazu Miwa, Chiya Kosaka, Yoji Taba and Takeo Abumiya
Molecular Pharmacology November 1, 1999, 56 (5) 938-946; DOI: https://doi.org/10.1124/mol.56.5.938

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Research ArticleArticle

Tumor Suppressor p53 But Not cGMP Mediates NO-Induced Expression of p21 Waf1/Cip1/Sdi1 in Vascular Smooth Muscle Cells

Akio Ishida, Toshiyuki Sasaguri, Yoshikazu Miwa, Chiya Kosaka, Yoji Taba and Takeo Abumiya
Molecular Pharmacology November 1, 1999, 56 (5) 938-946; DOI: https://doi.org/10.1124/mol.56.5.938
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