Characterization of the NADPH oxidase complex in human leiomyoma and normal myometrial smooth muscle cells and its role in PDGF and EGF signaling pathways

Reactive oxygen species have received an increasing amount of attention over the past decade, not only due to their role in oxidative damage, but also because of their participation as second messengers on the relay of many signaling pathways and their role in the development of numeours fibrotic diseases. This Ph.D. dissertation focused on testing the hypothesis that ROS are necessary components of the EGF and PDGF pathways in leiomyoma and normal myometrial SMCs. The main findings of this work were: 1) leiomyoma smooth muscle cells (LSMCs) and myometrial smooth muscle cells (MSMCs) produce ROS in response to EGF and PDGF; 2) ROS are necessary for EGF- and PDGF-induced LSMCs and MSMCs proliferation, and sufficient to induce LSMCs proliferation; 3) ROS are necessary and sufficient to induce a fraction of Erk1/2 activation in LSMCs and MSMCs; 4) NADPH oxidase components are expressed in leiomyoma and normal myometrial tissue; 5) PDGF induces translocation of p47phox into lipid rafts in LSMCs; 6) PKC mediates Erk1/2 activation by PDGF in MSMCs and LSMCs; 7) PKC activation alone is sufficient to induce ROS production in MSMCs and LSMCs; 8) hydrogen peroxide inhibits the activity of PTPases in LSMCs; 9) regulation of PTPase activity is important for myometrial and leiomyoma SMC proliferation. The findings suggest that ROS are necessary components of the EGF and PDGF pathways. There is also evidence that NADPH oxidase complex is the source of EGF and PDGF-induced ROS production, and that the mechanism of activation of this complex involves translocation of the subunit p47phox into lipid rafts as well as PKC activity. Furthermore, ROS might be acting by regulating protein tyrosine phosphatase enzymes, which in turn affect the proliferation of leiomyoma and myometrial SMCs. Based on the results obtained from my work I speculate that a subset of leiomyoma tumors may originate from a growth advantage acquired by myometrial SMCs that overexpress NADPH oxidase components leading to tumor development.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Animal Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2010

Author dc:creator

• Mesquita, Fernando S.

Contributors dc:contributor

• Nowak, Romana A.
• Bunick, David
• Miller, David J.
• Bagchi, Indrani C.
• Bahr, Janice M.

• Leiomyoma
• uterine fibroid
• NADPH oxidase
• Platelet-derived growth factor (PDGF)
• Epidermal growth factor (EGF)
• Nicotinamide adenine dinucleotide phosphate (NADPH)
• Reactive oxygen species (ROS)
• tyrosine phosphatase
• smooth muscle cells

Statement dc:rights

• Copyright 2010 Fernando S. Mesquita

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/15577

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/15577