The Transcriptional Program in the Response of Human Fibroblasts to Serum

Department of Biochemistry, Stanford University School of Medicine, Stanford CA 94305, USA.
Science (Impact Factor: 33.61). 02/1999; 283(5398):83-7.
Source: PubMed


The temporal program of gene expression during a model physiological response of human cells, the response of fibroblasts to serum, was explored with a complementary DNA microarray representing about 8600 different human genes. Genes could be clustered into groups on the basis of their temporal patterns of expression in this program. Many features of the transcriptional program appeared to be related to the physiology of wound repair, suggesting that fibroblasts play a larger and richer role in this complex multicellular response than had previously been appreciated.

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    • "We focus on time-course microarray experiments, where snapshots of gene expression are taken at predetermined instants of time. The observation interval is of biological interest such as a mitotic cell cycle [14] [15] [16] or the response of a tissue to an injury [17]. The main thrust of this paper is models that capture the joint probability distributions of temporal gene expression patterns and 0025-5564/© 2015 Elsevier Inc. "
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    ABSTRACT: We propose four probabilistic generative models for simultaneously modeling gene expression levels and gene ontology (GO) tags. Unlike previous approaches for using GO tags, the joint modeling framework allows the two sources of information to complement and reinforce each other. We fit our models to three time-course datasets collected to study biological processes, specifically blood vessel growth (angiogenesis) and mitotic cell cycles. The proposed models result in a joint clustering of genes and GO annotations. Different models group genes based on GO tags and their behavior over the entire time-course, within biological stages, or even individual time points. We show how such models can be used for biological stage boundary estimation de novo. We also evaluate our models on biological stage prediction accuracy of held out samples. Our results suggest that the models usually perform better when GO tag information is included. Copyright © 2015. Published by Elsevier Inc.
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    • "Mammalian fibroblasts require mitogens or growth factors to progress through the G 1 phase of the cell cycle. With the absence of mitotic signals, serum deprivation leads to a rapid exit from the cell cycle into the non-dividing G 0 phase (Holley et al., 1968; Iyer et al., 1999). "

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    • "Previous studies reported that bFGF promotes fibroblast proliferation, and proliferation is one of the key processes in wound healing [32]. To test the bFGF effects on cell proliferation of fibroblasts grown in HG medium, different concentrations of bFGF (50–400 ng/mL) were treated to cells that were grown in a 30 mM glucose-containing medium. "
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    ABSTRACT: One of the major symptoms of diabetes mellitus (DM) is delayed wound healing, which affects large populations of patients worldwide. However, the underlying mechanism behind this illness remains elusive. Skin wound healing requires a series of coordinated processes, including fibroblast cell proliferation and migration. Here, we simulate DM by application of high glucose (HG) in human foreskin primary fibroblast cells to analyze the molecular mechanism of DM effects on wound healing. The results indicate that HG, at a concentration of 30 mM, delay cell migration, but not cell proliferation. bFGF is known to promote cell migration that partially rescues HG effects on cell migration. Molecular and cell biology studies demonstrated that HG enhanced ROS production and repressed JNK phosphorylation, but did not affect Rac1 activity. JNK and Rac1 activation were known to be important for bFGF regulated cell migration. To further confirm DM effects on skin repair, a type 1 diabetic rat model was established, and we observed the efficacy of bFGF on both normal and diabetic rat skin repair. Furthermore, proteomic studies identified an increase of Annexin A2 protein nitration in HG-stressed fibroblasts and the nitration was protected by activation of bFGF signaling. Treatment with FGFR1 and JNK inhibitors delayed cell migration and increased Annexin A2 nitration levels, indicating that Annexin A2 nitration is modulated by bFGF signaling via activation of JNK. Together with these results, our data suggests that the HG-mediated delay of cell migration is linked to the inhibition of bFGF signaling, specifically through JNK suppression.
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