Involvement of MEKK1/ERK/P21Waf1/Cip1 signal transduction pathway in inhibition of IGF-I-mediated cell growth response by methylglyoxal

Jun Du, Shaohui Cai, Haruhiko Suzuki, Anwarul A. Akhand, Xiuyang Ma, Yoshikazu Takagi, Toshio Miyata, Izumi Nakashima, Fumihiko Nagase

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

The abnormal accumulation of methylglyoxal (MG), a physiological glucose metabolite, is strongly related to the development of diabetic complications by affecting the metabolism and functions of organs and tissues. These disturbances could modify the cell response to hormones and growth factors, including insulin-like growth factor-1 (IGF-I). In this study, we investigated the effect of MG on IGF-I-induced cell proliferation and the mechanism of the effect in two cell lines, a human embryonic kidney cell line (HEK293), and a mouse fibroblast cell line (NIH3T3). MG rendered these cells resistant to the mitogenic action of IGF-I, and this was associated with stronger and prolonged activation of ERK and over-expression of P21Waf1/Cip1. The synergistic effect of MG with IGF-I in activation of ERK was completely abolished by PD98059 but not by a specific PI3K inhibitor, LY294002, or a specific PKC inhibitor, bisindolylmaleimide. Blocking of Raf-1 activity by expression of a dominant negative form of Raf-1 did not reduce the enhancing effect of MG on IGF-I-induced activation of ERK. However, transfection of a catalytically inactive form of MEKK1 resulted in inactivation of the MG-induced activation of ERK and partial inhibition of the enhanced activation of ERK and over-expression of p21Waf1/Cip1 induced by co-stimulation of MG and IGF-I. These results suggested that the alteration of intracellular milieu induced by MG through a MEKK1-mediated and PI3K/PKC/Raf-1-independent pathway resulted in the modification of cell response to IGF-I for p21Waf1/Cip1-mediated growth arrest, which may be one of the crucial mechanisms for MG to promote the development of chronic clinical complications in diabetes.

Original languageEnglish
Pages (from-to)1235-1246
Number of pages12
JournalJournal of Cellular Biochemistry
Volume88
Issue number6
DOIs
Publication statusPublished - 2003 Apr 15
Externally publishedYes

Keywords

  • ERK
  • IGF-I
  • MEKK1
  • Methylglyoxal
  • P21

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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