Homocysteine and other biothiols activate serum response factor

Y. J. Suzuki, S. S. Shi, R. M. Day, M. Chedid, J. B. Blumberg

Research output: Contribution to journalArticlepeer-review

Abstract

Homocysteine (HCys), a sulfur-containing amino acid that is generated during methionine metabolism, has been implicated as an independent risk factor for arteriosclerosis. The mechanism of HCys action has been attributed, in part, to a cell growth promoting property, and HCys has been shown to induce c-fos proto-oncogene. To understand molecular mechanisms of HCys-signaling for c-fos expression and cell growth, we examined the ability of HCys to activate serum response factor (SRF). Electrophoretic mobility shift assays revealed that 20 uM D,L-HCys elicits enhancement of DNA binding activity of SRF but not Stat-1 in serum-deprived NIH/3T3 cells. The SRF activation was transient with maximal activation occurring at 30 min. Other biologically relevant Ihiols such as cysteine and lipoic acid also elicited SRF activation. Constitutively enhanced activity of SRF in cells expressing active mutant of Ras (Lys-12) was inhibited by HCys, possibly through reduction of Rac-dependent production of reactive oxygen species as previously described (Irani, et al.. Science 275:1649, 1997). Further, HCys, cysteine and lipoic acid activated ERK as determined by western blot analysis using the antibody for phosphorylated p44/p42 MAP kinases (Tyr-204). However, ERK activation by these biothiols was not detected in cells expressing dominant negative mutant Ras (Asn-17). Therefore, thiol-dependent activation of the Ras-ERK-SRF axis of signal transduction may be involved in HCys-induced pathogenesis.

Original languageEnglish (US)
Pages (from-to)A1482
JournalFASEB Journal
Volume12
Issue number8
StatePublished - 1998

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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