title: 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 p21(waf1/cip1).
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 p21(waf1/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.
authors.affiliation: Department of Pathology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Bhanoori
authors.forename: Chandrahasa R
authors.initials: CR
authors.lastname: Yellaturu
authors.forename: Salil K
authors.initials: SK
authors.lastname: Ghosh
authors.forename: Aviv
authors.initials: A
authors.lastname: Hassid
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Jennings
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D000478:Alkylation; D000818:Animals; D001483:Base Sequence; D000077214:Becaplermin; D020170:Caspase 1 / Q000378:metabolism*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D008297:Male; D008934:Mitogens / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D013438:Sulfhydryl Compounds; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D000077214:Becaplermin; D017027:Protein Tyrosine Phosphatases; D020170:Caspase 1