Regulation of PDGF production and ERK activation by estrogen is associated with TSC2 gene expression
| Autor: | Barry L. Fanburg, Deborah S. Hunter, Geraldine A. Finlay, K. E. Paulson, Cheryl L. Walker |
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| Rok vydání: | 2003 |
| Předmět: |
MAPK/ERK pathway
Physiology medicine.drug_class Models Biological Receptor Platelet-Derived Growth Factor beta Mice Gene expression Nitriles Tuberous Sclerosis Complex 2 Protein medicine Tumor Cells Cultured Animals Phosphorylation Loss function Platelet-Derived Growth Factor biology Cell growth Tumor Suppressor Proteins Estrogens Muscle Smooth Cell Biology Tyrphostins Rats Gene Expression Regulation Neoplastic Repressor Proteins Autocrine Communication Cell Transformation Neoplastic Estrogen Mitogen-activated protein kinase Cancer research biology.protein Female Endothelium Vascular TSC2 Mitogen-Activated Protein Kinases Platelet-derived growth factor receptor Cell Division Signal Transduction |
| Zdroj: | American journal of physiology. Cell physiology. 285(2) |
| ISSN: | 0363-6143 |
| Popis: | Mechanisms that regulate the growth response to estrogen (17β-estradiol, E2) are poorly understood. Recently, loss of function of the tuberous sclerosis complex 2 ( TSC2) gene has been associated with E2-related conditions that are characterized by benign cellular proliferation. We examined the growth response to E2in vascular smooth muscle cells (VSMCs) that possess wild-type TSC2 and compared them with ELT-3 smooth muscle cells that do not express TSC2.In TSC2-expressing VSMCs, growth inhibition in response to E2was associated with downregulation of platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), and limited activation of extracellular signal-regulated kinase (ERK). In contrast, the growth-promoting effect of E2in TSC2-null ELT-3 cells was associated with induction of PDGF, robust phosphorylation of PDGFR, and sustained activation of ERK. Furthermore, in ELT-3 cells, cellular growth and ERK activation by E2were inhibited by the PDGFR inhibitor tyrphostin AG 17 and by PDGF-neutralizing antibody. These results demonstrate that autocrine production of PDGF and augmentation of the ERK pathway leads to estrogen-induced cellular proliferation in TSC2-null cells, a pathway that was downregulated in cells that express TSC2. Understanding the mechanisms that regulate the diverse responses to the steroid hormone estrogen could lead to novel approaches to the treatment of estrogen-related diseases that are characterized by aberrant cell proliferation. |
| Databáze: | OpenAIRE |
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