• Biomolecules & Therapeutics
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• v.21 no.5
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• pp.323-331
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• 2013

TGF-${\beta}$ pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-${\beta}$ (TGF-${\beta}$) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-${\beta}$ related functional contexts. This review discusses the molecular mechanism of the TGF-${\beta}$ pathway and describes the different ways of tumor suppression and promotion by TGF-${\beta}$. In the last part of the review, the data on targeting TGF-${\beta}$ pathway for cancer treatment is assessed. The TGF-${\beta}$ inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.27 no.2
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• pp.123-130
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• 2005

Many of the molecular and genotypic events taking place at the osteoblast cell level during bone-implant integration are still largely unknown. The objective of this study was to examine expression patterns of TGF-$\beta$ and IGF-I related genes during bone-implant integration. Titanium implants with machined surface were placed into 8 rabbit tibias. At 3rd, 7th, 14th, 28th day after implantation, the expression pattern of TGF-$\beta$ and IGF-I genes in bone with or without implant was examined using reverse transcriptase-polymerase chain reaction (RT-PCR). At the same time, histomorphometric analysis was evaluated, respectively. The bone-to-implant contacts (BIC) of experimental groups were 5.2%, 6.2%, 6.6%, 24.6% at 3rd, 7th, 14th, 28th day. This indicated that newly formed bone increased at the implant surface in bone marrow space after implantation. The expressions of TGF-$\beta$ and IGF-I were higher in implantation groups than untreated control groups during all experimental days. The increased expression of TGF-$\beta$ and IGF-I genes may be associated with the increased bone-to-implant contact. This result provided the evidence for existing biologic differences in tissue response after implantation and helped us to understand molecular biologic processes in tissue-implant integration.

• Archives of Pharmacal Research
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• v.22 no.1
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• pp.1-8
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• 1999

Transforming growth factor-$\beta$ (TGF-$\beta$) is the prototypical multifunctional cytokine, participating in the regulation of vital cellular activities such as proliferation and differentiations as well as a number of basic physiological functions. The effects of TGF-$\beta$ are critically dependent on the expression and distribution of a family of TGF-$\beta$ receptors, the TGF-$\beta$ types I, II, and III. It is now known that a wide variety of human pathology can be caused by aberrant expression and function of these receptors. the coding sequence of the type II receptor (RII) appears to render it uniquely susceptible to DNA replication errors in the course of normal cell division. By virtue of its key role in the regulation of cell proliferation, TGF-$\beta$ RII should be considered as a tumor suppressor gene. High levels of mutation in the TGF-$\beta$ RII gene have been observed in a wide range of primarily epithelial malignancies, including colon and gastric cancer. It appears likely that mutation of the TGF-$\beta$ RII gene may be a very critical step in the pathway of carcinogenesis.

• Journal of Microbiology
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• v.35 no.4
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• pp.341-346
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• 1997

In order to express recombinant porcine TGF-${\beta}1$ protein in a baculovirus expression system the entire TGF-${\beta}1$gene containing extra amino acids at the N terminus was cloned into pFBa and pFBb of the Bac-To-$Bac^{TM}$ baculovirus expression system. One of the clones contained 106 extra amino acids and was designated pFBa-106 TGF-${\beta}1$, and the other had 28 extra amino acids and was designated pFBb-28 TGF-${\beta}1$. The orientation of the gene was identified with restriction enzyme mapping and PCR with internal TGF-${\beta}1$ primers. Sf-9 cells were infected at a m.o.i. of 10 by the recombinant viruses generated from the two expected sizes of 55 kD and 46.4kD. these precursor forms of TGF-${\beta}1$ with a polyclonal antibody against human TGF-${\beta}1$. No mature form of TGF-${\beta}1$ protein was detected on SDS gels and an immunoblot indicated that TGF-${\beta}1$ precursor is not properlu processed in insect cells.

• Reproductive and Developmental Biology
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• v.30 no.4
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• pp.271-277
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• 2006

Transforming growth $factor-{\beta}\;(TGF-{\beta})$ has been shown to have a positive effect on in vitro fertilization (IVF) and has been reported to stimulate meiosis at follicular level in variety of species. The study was designed to determine the expression patterns of $TGF-{\beta}1,\;TGF-{\beta}$ receptors type I, II and Smads gene in bovine oocytes and embryos. $TGF-{\beta}1$ and their receptors were observed in the unfertilized oocytes. $TGF-{\beta}1$ and type II receptor were not expressed at the blastocyst stage, however, only type I receptor was exclusively observed at the same stage. The blastocyst stage, in particular, showed high levels of mRNA expression patterns containing a $TGF-{\beta}1$ type I receptor. The mRNA expression pattern of Smad 2 at all stages of embryonic development was similar in all respect with $TGF-{\beta}1$ type I receptor. On the contrary, Smad 3 and 4 were expressed with high and low level mRNA at the blastocyst stage. In conclusion. it is suggested that $TGF-{\beta}1$ signaling may be regarded as an important entity during the preimplantation embryo development.

• Journal of the Korean Society of Food Science and Nutrition
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• v.30 no.2
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• pp.307-313
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• 2001

Iron excess is known to affect long-term iron accumulation and tissue change such as fibrosis in liver. To determine the changes of expression level of genes associated with fibrosis by short-term iron exposure, we measured liver mRNA levels by reverse transcription polymerase chain reaction (RT-PCR) in rats fed dietary carbonyl iron (3%, wt/wt) for 9 weeks. The results showed that the expression of the collagen (I, III) and transforming growth factor (TGF)-$\beta$I mRNAs was enhanced in high-dose iron treated rat, compared to normal-dose iron treated rat. An electron microscopy study revealed that excess iron caused increase of collagen fibrils in liver. The cell shapes and compositions of hepatocytes and extracellular matrix(ECM) in liver were changed by the iron-treatment. Also, necrosised hepatocytes were broadly seen in ECM. Taken together, we suggest that iron overload affects changes of collagen and TGF-$\beta$I gene expression and these changes are associated with liver fibrogenesis.

• Molecules and Cells
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• v.38 no.1
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• pp.20-25
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• 2015

TGF-${\beta}$ regulates pleiotropic cellular responses including cell growth, differentiation, migration, apoptosis, extracellular matrix production, and many other biological processes. Although non-Smad signaling pathways are being increasingly reported to play many roles in TGF-${\beta}$-mediated biological processes, Smads, especially receptor-regulated Smads (R-Smads), still play a central mediatory role in TGF-${\beta}$ signaling for epithelial-mesenchymal transition. Thus, the biological activities of R-Smads are tightly regulated at multiple points. Inhibitory Smad (I-Smad also called Smad7) acts as a critical endogenous negative feedback regulator of Smad-signaling pathways by inhibiting R-Smad phosphorylation and by inducing activated type I TGF-${\beta}$ receptor degradation. Roles played by Smad7 in health and disease are being increasingly reported, but the molecular mechanisms that regulate Smad7 are not well understood. In this study, we show that E3 ubiquitin ligase Itch acts as a positive regulator of TGF-${\beta}$ signaling and of subsequent EMT-related gene expression. Interestingly, the Itch-mediated positive regulation of TGF-${\beta}$ signaling was found to be dependent on Smad7 ubiquitination and its subsequent degradation. Further study revealed Itch acts as an E3 ubiquitin ligase for Smad7 polyubiquitination, and thus, that Itch is an important regulator of Smad7 activity and a positive regulator of TGF-${\beta}$ signaling and of TGF-${\beta}$-mediated biological processes. Accordingly, the study uncovers a novel regulatory mechanism whereby Smad7 is controlled by Itch.

• The Journal of Korean Medicine
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• v.24 no.2
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• pp.1-11
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• 2003

Objectives : The aim of this study was to characterize the effect of Injinchunggan-tang on $TGF-{\beta}1-induced$ hepatic fibrosis. Methods : mRNA and protein expression levels of $TGF-{\beta}1$ in Injinchunggan-tang-treated HepG2 cells were compared to untreated cells using quantitative RT-PCR and ELISA assay, respectively. mRNA expression levels of the TGF-1 pathway genes (TR-1, TR-II, Smad2, Smad3, Smad4, and PAI-1) and fibrosis-associated genes (CTGF, fibronectin, and collagen type 1) were evaluated by quantitative RT-PCR. The effect of Injinchunggan-tang on cell proliferation of T3891 human fibroblast was evaluated using [$^3H$]thymidine incorporation assay. Results : Expression of $TGF-{\beta}1$ mRNA and protein was inhibited by Injinchunggan-tang in a dose- and time-dependent manner. Whereas $TGF-{\beta}1-mediated$ induction of PAI-1 was suppressed by Injinchunggan-tang, expression of the $TGF-{\beta}1$ pathway genes such as TR-1, TR-II, Smad2, Smad3, and Smad4 was not affected by Injinchunggan-tang treatment. Injinchunggan-tang was found to inhibit $TGF-{\beta}1-induced$ cell proliferation of T3891 human fibroblast, and also abrogated $TGF-{\beta}1-mediated$ transcriptional up-regulation of CTGF, fibronectin, and collagen type I. Conclusions : This study strongly suggests that the liver cirrhosis-suppressive activity of Injinchunggan-tang may be derived at least in part from its inhibitory effect on $TGF-{\beta}1$ functions, such as blockade of $TGF-{\beta}1$ stimulation of fibroblast cell proliferation and fibrosis-related gene expression as well as expression of $TGF-{\beta}1$ itself.

• Archives of Plastic Surgery
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• v.33 no.4
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• pp.427-432
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• 2006

Purpose: Noninflammatory synovial fibrosis has been noted for main causal factor of carpal tunnel syndrome (CTS). Recently, there are some reports that heparin have not only anti-coagulative effect but also anti-inflammatory and anti-fibrotic potential and have an effect on interstitial pulmonary fiborosis. Authors examined whether heparin affects pathogenesis of CTS. Methods: First, heparin was administered to fibroblast that was cultured from patient's transverse carpal ligament. Secondly, we evaluated the expression from genes of type I, III collagen, TGF ${\beta}$ isoforms and MMP. Fibroblasts were isolated and cultured from transverse carpal ligaments of 5 patients with CTS. Heparin (0, 1, 10,$100{\mu}g/ml$) was administered to cultured fibroblast and reverse transcription PCR for mRNA expression of type I, III collagen, TGF-${\beta}$ isoforms and MMP was done. Results: Heparin suppressed gene expression of type I, III collagen and TGF-${\beta}1$, ${\beta}3$ but promoted gene expression of TGF-${\beta}2$ and MMP-2. Conclusion: Heparin directly suppress gene expression of type I, III collagen. But, It is undetermined that heparin can present it's effect mediated by TGF ${\beta}$ isoforms or MMP.

• Asian-Australasian Journal of Animal Sciences
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• v.32 no.4
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• pp.477-484
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• 2019

Objective: We aimed to observe hair follicle (HF) development in the dorsal skin and elucidate the expression patterns of genes and proteins related to skin and HF development in Rex rabbits from birth to 8 weeks of age. Methods: Whole-skin samples were obtained from the backs of Rex rabbits at 0, 2, 4, 6, and 8 weeks of age, the morphological development of primary and secondary HFs was observed, and the gene transcript levels of insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), bone morphogenetic protein 2 (BMP2), transforming growth factor ${\beta}-1$, 2, and 3 ($TGF{\beta}-1$, $TGF{\beta}-2$, and $TGF{\beta}-3$) were examined using quantitative real-time polymerase chain reaction (PCR). Additionally, Wnt family member 10b (Wnt10b) and ${\beta}$-Catenin gene and protein expression were examined by quantitative real-time PCR and western blot, respectively. Results: The results showed significant changes in the differentiation of primary and secondary HFs in Rex rabbits during their first 8 weeks of life. The IGF-I, EGF, $TGF{\beta}-2$, and $TGF{\beta}-3$ transcript levels in the rabbits were significantly lower at 2 weeks of age than at birth and gradually increased thereafter, while the BMP2 and $TGF{\beta}-1$ transcript levels at 2 weeks of age were significantly higher than those at birth and gradually decreased thereafter. ${\beta}$-Catenin gene expression was also significantly affected by age, while the Wnt10b transcript level was not. However, the Wnt10b and ${\beta}$-catenin protein expression levels were the lowest at 2 and 4 weeks of age. Conclusion: Our data showed that a series of changes in HFs in dorsal skin occurred during the first 8 weeks. Many genes, such as IGF-I, EGF, BMP2, $TGF{\beta}-1$, $TGF{\beta}-2$, $TGF{\beta}-3$, and ${\beta}$-Catenin, participated in this process, and the related proteins Wnt10b and ${\beta}$-Catenin in skin were also affected by age.