Thiol alkylation inhibits the mitogenic effects of platelet-derived growth factor and renders it proapoptotic via activation of STATs and p53 and induction of expression of caspasel and p21waf1/cip1

Manjula Bhanoori, Chandrahasa R. Yellaturu, Salil K. Ghosh, Aviv Hassid, Lisa K. Jennings, Rao Gadiparthi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Thiols provide the major intracellular redox milieu and can undergo reversible oxidation and reduction. To understand the role of thiols in redox signaling events, we have studied the effect of N-ethylmaleimide, a specific thiol alkylating agent, on platelet-derived growth factor-BB (PDGF-BB)-induced mitogenesis in vascular smooth muscle cells (VSMC). Thiol alkylation inhibited PDGF-BB-induced expression of the Fos and Jun family proteins and AP-1 activity in VSMC. Thiol alkylation also inhibited PDGF-BB-induced expression of cyclin A and growth in these cells. In contrast, thiol alkylation enhanced and sustained the effect of PDGF-BB on the activation of the Jak STAT pathway, and this event was correlated with inhibition of protein tyrosine phosphatase IB activity. Thiol alkylation via inducing the expression of p21waf1/cip1 in a STAT1- and p53-dependent manner antagonized the downregulation of this cell cycle inhibitory molecule by PDGF-BB. The inhibition of AP-1 and activation of STATs, particularly STAT1, by thiol alkylation correlated with increased production of active caspase 1 and apoptosis in VSMC. Together, these findings suggest a role for thiols in mediating mitogenic and/or apoptotic signaling events in VSMC. These results also show that a sustained change in the intracellular thiol redox state can convert a mitogen into a death promoter.

Original languageEnglish (US)
Pages (from-to)117-130
Number of pages14
JournalOncogene
Volume22
Issue number1
DOIs
StatePublished - Jan 9 2003

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Platelet-Derived Growth Factor
Alkylation
Sulfhydryl Compounds
Vascular Smooth Muscle
Oxidation-Reduction
Smooth Muscle Myocytes
Transcription Factor AP-1
Cyclin A
Caspase 1
Protein Tyrosine Phosphatases
Ethylmaleimide
Alkylating Agents
Mitogens
Cell Cycle
Down-Regulation
platelet-derived growth factor BB
Apoptosis

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Thiol alkylation inhibits the mitogenic effects of platelet-derived growth factor and renders it proapoptotic via activation of STATs and p53 and induction of expression of caspasel and p21waf1/cip1. / Bhanoori, Manjula; Yellaturu, Chandrahasa R.; Ghosh, Salil K.; Hassid, Aviv; Jennings, Lisa K.; Gadiparthi, Rao.

In: Oncogene, Vol. 22, No. 1, 09.01.2003, p. 117-130.

Research output: Contribution to journalArticle

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abstract = "Thiols provide the major intracellular redox milieu and can undergo reversible oxidation and reduction. To understand the role of thiols in redox signaling events, we have studied the effect of N-ethylmaleimide, a specific thiol alkylating agent, on platelet-derived growth factor-BB (PDGF-BB)-induced mitogenesis in vascular smooth muscle cells (VSMC). Thiol alkylation inhibited PDGF-BB-induced expression of the Fos and Jun family proteins and AP-1 activity in VSMC. Thiol alkylation also inhibited PDGF-BB-induced expression of cyclin A and growth in these cells. In contrast, thiol alkylation enhanced and sustained the effect of PDGF-BB on the activation of the Jak STAT pathway, and this event was correlated with inhibition of protein tyrosine phosphatase IB activity. Thiol alkylation via inducing the expression of p21waf1/cip1 in a STAT1- and p53-dependent manner antagonized the downregulation of this cell cycle inhibitory molecule by PDGF-BB. The inhibition of AP-1 and activation of STATs, particularly STAT1, by thiol alkylation correlated with increased production of active caspase 1 and apoptosis in VSMC. Together, these findings suggest a role for thiols in mediating mitogenic and/or apoptotic signaling events in VSMC. These results also show that a sustained change in the intracellular thiol redox state can convert a mitogen into a death promoter.",
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