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Title	Transforming Growth Factor ß1 (tgf-ß1) signaling mechanisms in human dermal diploid fibroblasts: phosphorylation of nuclear proteins and involvement in cell proliferation
Author	Lubinus, Manuel Duran
Date	1994
Affiliation/College	College of Graduate Studies
Department	Microbiology and Immunology
Extent	viii, 115 leaves : illustrations; 29 cm
Source	QU 107 L929t 1994
Subject.MeSH	Academic Dissertations Academic Dissertations--South Carolina Phosphorylation Cell Proliferation Transforming Growth Factors Growth Substances Receptors, Growth Factor Fibroblasts
Collection	MUSC Theses and Dissertations
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright is held by the author.
Language	English
Type	Text
Format	application/pdf
Media Type	Manuscripts
Resource Identifier	mtd1994_lubinus_md
Abstract	Transforming Growth Factor gl (TGF-ß) is a pleiotropic cytokine involved in mesenchymal cell proliferation and regulation of extracellular matrix gene expression. We have found that an eight hour pretreatment (priming) of human adult fibroblasts with TGFßI (1 ng/ml) selectively potentiates mitogenic responses to cytokines: TNFα (4.2-fold), interleukin-6 (3.0 fold), and endothelin-l (2.8 fold). An antibody against platelet-derived growth factor AA (PDGF-AA) partially blocked priming, with differential inhibitory effects noted with each cytokine. When the signaling mechanisms of the PDGF isoforms were compared in these cells, both PDGF-AA and PDGF-BB were shown to be equally potent activators of mitogen-activated protein kinase (MAPK), an enzyme involved in the G0-G1 transition. In marked contrast, the isoforms differed in their mitogenic potential: PDGF-BB elicited a strong mitogenic response, while PDGF AA had no significant effect on DNA synthesis in human dermal fibroblasts. To characterize TGF-ß signaling pathways in dermal fibroblasts, anion exchange chromatography along with one-dimensional electrophoresis was employed to detect phosphorylation of two proteins of 350 and 43 kD respectively in [32P]orthophosphate labeled cells after stimulation with TGF-ß. The 43kd protein was shown to correspond to the cAMP responsive element binding protein (CREB). Autophosphorylation of the TGF-ß type II receptor upon TGF-ß addition was also observed. Relevant to its growth modulation activity, TGF-ß decreased the level of retinoblastoma protein (Rb), a tumor suppressor gene, while inducing its phosphorylation in newborn fibroblasts. TGF-ß also induced phosphorylation of the zinc-finger transcription factor Sp1, as well as activation of an Sp1kinase, the DNA-dependent protein kinase. These studies indicate novel pathways for TGF-ß at the nuclear level and might contribute to the better understanding of TGF-ß1 pathophysiology in fibrotic diseases such as scleroderma.

Transforming Growth Factor ß1 (tgf-ß1) signaling mechanisms in human dermal diploid fibroblasts: phosphorylation of nuclear proteins and involvement in cell proliferation

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