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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 caspase1 and p21waf1/cip1

Oncogene volume 22, pages 117–130 (2003)Cite this article

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 lB 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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Acknowledgements

We are thankful to Drs Ralph A Bradshaw, Jonathan Chernoff, Michael Karin, Bert Vogelstein and Howard Young for providing us with pFSlDM, pJ3H-PTP435, pCOLL-CAT, pWWW-Luc, p53R175H and pSIE-CAT, respectively. This work was supported in part by a grant from the NIH (HL64165) to GNR.

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Authors and Affiliations

  1. Department of Physiology, The University of Tennessee Health Science Center, Memphis, 38163, TN, USA

    Manjula Bhanoori, Chandrahasa R Yellaturu, Salil K Ghosh, Aviv Hassid & Gadiparthi N Rao

  2. Center for Vascular Biology, The University of Tennessee Health Science Center, Memphis, 38163, TN, USA

    Aviv Hassid, Lisa K Jennings & Gadiparthi N Rao

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  1. Manjula Bhanoori
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Correspondence to Gadiparthi N Rao.

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Bhanoori, M., Yellaturu, C., Ghosh, S. et al. 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 caspase1 and p21waf1/cip1. Oncogene 22, 117–130 (2003). https://doi.org/10.1038/sj.onc.1206065

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