論文

査読有り
2008年7月

Activation of protein kinase G increases the expression of p21(CIP1), p27(KIP1), and Histidine triad protein 1 through Sp1

CANCER RESEARCH
  • Bo Cen
  • ,
  • Atsuko Deguchi
  • ,
  • I. Bernard Weinstein

68
13
開始ページ
5355
終了ページ
5362
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/0008-5472.CAN-07-6869
出版者・発行元
AMER ASSOC CANCER RESEARCH

The anticancer role of cyclic guanosine 3',5'-monophosphate (cGMP)-dependent protein kinase G (PKG) has become of considerable interest, but the underlying mechanisms are not fully established. In this study, we examined the effects of activation of PKG on the expression of three tumor suppressor proteins in human SW480 colon cancer cells. Our results revealed that treatment with cell permeable cGMP derivatives, or the cGMP phosphodiesterase inhibitor sulindac sulfone (exisulind, aptosyn, hereafter called exisulind) led to increased expression of the tumor suppressor proteins p21(CIP1), p27(KIP1), and Histidine triad protein 1 (HINTI), and their corresponding mRNAs. Overexpression of PKG I beta also caused increased expression of the p21(CIP1), p27(KIP1), and HINT1 proteins. Both the p21(CIP1), p27(KIP1) promoters contain Sp1 binding sites and they were activated by PKG in luciferase reporter assays. Specific Sp1 sites in the p21 and p27 promoters were sufficient to mediate PKG-induced luciferase reporter activity, suggesting an interaction between Sp1 and PKG. Indeed, we found that PKG can phosphorylate Sp1 on serine residue(s) and this resulted in transcriptional activation of Sp1. Knockdown of Sp1 expression with siRNA inhibited the increased expression of p21(CIP1), p27(KIP1), and HINT1 induced by the cGMP derivative 8-pCPT-cGMP in SW480 cells. These novel effects of PKG activation on the expression of three tumor suppressor genes may explain, at least in part, the anticancer effects of activation of PKG. They also provide a rationale for further developing activators of PKG for the prevention and treatment of cancer.

Web of Science ® 被引用回数 : 30

リンク情報
DOI
https://doi.org/10.1158/0008-5472.CAN-07-6869
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/18593937
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000257415300049&DestApp=WOS_CPL

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