[show abstract][hide abstract] ABSTRACT: Adiponectin plays important roles in the regulation of insulin action and metabolism of glucose and lipids. We investigated whether ADIPOQ genetic variants are associated with serum lipid levels in Korean children and whether those influences might be modulated by dietary factors such as dietary monounsaturated fatty acid to saturated fatty acid ratio (MUFA:SFA).
The study included a population-based sample of 687 children aged 7-11 years in Gwacheon city, Kyunggi Province, Korea. Anthropometric and biochemical measurements and ADIPOQ genotype (-11377 C/G, +45 T/G, and +276 G/T) were determined. Dietary intake was estimated with a self reported 3-day food diary. The -11377 G allele carriers had significantly higher serum total cholesterol and LDL cholesterol compared to non-carriers. When dietary MUFA:SFA ratio was dichotomized (MUFA:SFA ≥1 or <1), the aggravating effects of the minor allele on serum total and LDL cholesterol were only present when the MUFA:SFA ratio was <1. Additionally, we observed that the ADIPOQ haplotype influenced serum total and LDL cholesterol levels. G-T-G haplotype carriers had higher total and LDL cholesterol levels than non-G-T-G carriers. The deleterious effect of ADIPOQ G-T-G haplotype to increase serum total and LDL cholesterol could be seen only when the MUFA:SFA ratio was <1.
In this present study, we found interaction effects between ADIPOQ genetic variants and dietary MUFA:SFA ratio on serum lipid levels in Korean children. These results suggest that individual genetic information and dietary fatty acid intake information should be assessed together to achieve an effective outcome for reducing the atherogenic lipid profile.
[show abstract][hide abstract] ABSTRACT: Currently, serum biomarkers, which are sufficiently sensitive and specific for early detection and risk classification of gastric adenocarcinoma do not exist. Therefore, this study identified a panel of serum biomarkers for the diagnosis of gastric adenocarcinoma.
A 29-plex array platform with 29 biomarkers, consisting of 11 proteins discovered through proteomics and 18 previously known to be cancer-associated, was constructed. A test/training set consisting of 120 gastric adenocarcinoma and 120 control samples were examined. After 13 proteins were selected as candidate biomarkers, multivariate classification analyses were used to identify algorithms for diagnostic biomarker combinations. These algorithms were independently validated using a set of 95 gastric adenocarcinoma and 51 control samples.
Epidermal growth factor receptor (EGFR), pro-apolipoprotein A1 (proApoA1), apolipoprotein A1, transthyretin (TTR), regulated upon activation, normally T-expressed and presumably secreted (RANTES), D-dimer, vitronectin (VN), interleukin-6, α-2 macroglobulin, C-reactive protein and plasminogen activator inhibitor-1 were selected as classifiers in the two algorithms. These algorithms differentiated between the majority of gastric adenocarcinoma and control serum samples in the training/test set with high accuracy (>88%). These algorithms also accurately classified in the validation set (>85%).
Two panels of combinatorial biomarkers, including EGFR, TTR, RANTES, and VN, are developed, which are less invasive method for the diagnosis of gastric adenocarcinoma. They could supplement clinical gastroscopic evaluation of symptomatic patients to enhance diagnostic accuracy.
British Journal of Cancer 02/2012; 106(4):733-9. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: The pattern of gastric cancer in the Western world is changing, with an increased proportion of tumours in the upper stomach. The aim of this study was to investigate changes in clinicopathological features and survival of patients with resected gastric cancer at a single institution, in an area of high incidence in the Far East.
Clinical features and pathological findings were compared in patients with gastric cancer who underwent gastrectomy at Seoul National University Hospital during four consecutive periods (1986-1990, 1991-1995, 1996-2000 and 2001-2006).
There were 12 026 patients. The mean age increased from 53·4 years in the first period to 57·4 years in the last (P < 0·001). The proportion of patients aged 70 years or older also increased, reaching 16·1 per cent in the final period. Upper-third cancer increased from 5·3 per cent in the first period to 14·0 per cent in the fourth (P < 0·001). Early gastric cancer (pathological T1) increased continuously over the four time intervals, from 24·8 to 48·9 per cent (P < 0·001). The overall 5-year survival rate increased from 64·0 per cent in the first period to 73·2 per cent at the end (P < 0·001), and this survival improvement was apparent in patients aged 40 years or more.
The mean age of patients with gastric cancer has increased during the past 20 years. The proportion of early gastric cancer and overall survival have gradually increased, especially in patients aged over 40 years.
British Journal of Surgery 11/2010; 98(2):255-60. · 4.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study aimed to determine the appropriate extent of lymph node (LN) dissection in gastric cancer by analysing LN metastasis patterns from prospectively collected topographical data on nodal status at Seoul National University Hospital, Korea.
The metastasis rate for each LN station was analysed according to the depth of tumour invasion in patients with primary lower-third gastric cancer who underwent curative gastrectomy. The Maruyama Index of unresected disease (MI) was calculated using the WinEstimate(®) program with simulation of various extents of LN dissection.
LN metastasis in mucosal cancer was rare; 2·6 per cent of patients had a MI of more than 5 with simulation of D1 plus station 7 dissection, whereas 0·9 per cent had a MI above 5 with D1 plus stations 7 and 8a. In submucosal cancer, 3·3 per cent of tumours metastasized to level 2 LN stations outside the range of D1 plus stations 7, 8a and 9. The proportion of patients with a MI above 5 was 9·0 per cent with D1 plus stations 7, 8a and 9 dissection. The nodal metastasis rate was higher at level 1 and 2 for muscularis propria or deeper cancers.
D1 dissection plus stations 7 and 8a for mucosal cancer, and D2 dissection for cancers of the muscularis propria or deeper seems appropriate. For submucosal cancer, an expanded dissection to the D2 level should be considered to ensure complete removal of metastatic LNs.
British Journal of Surgery 10/2010; 98(1):65-72. · 4.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although substance P (SP) stimulates bone resorption activity and this is reported to be correlated with the degree of periodontal inflammation, it is unclear how human periodontal ligament cells regulate neuropeptide-induced osteoclastogenesis or the possible involvement of heme oxygenase-1 (HO-1) might be. This study examines how SP affects osteoprotegerin (OPG) and RANKL expression via HO-1.
Using immortalized human periodontal ligament cells, the effects of SP on the expression of HO-1, RANKL and OPG mRNA and proteins were determined by RT-PCR and western blotting, respectively. Various concentrations of SP (10(-7), 10(-8), 10(-9) and 10(-10) m) were added to the medium, and the cells were treated for 0, 0.25, 0.5, 1, 2 and 3 d.
Substance P upregulated RANKL and HO-1 and downregulated OPG mRNA and protein expression in periodontal ligament cells, in a concentration- and time-dependent manner. A HO-1 inducer inhibited both the upregulation of RANKL expression and downregulation of OPG expression by SP in periodontal ligament cells. By contrast, treatment with a HO-1 inhibitor or HO-1 small interferring RNA (siRNA) enhanced SP-stimulated RANKL expression. Inhibitors of ERK and p38 MAP kinases, phosphoinositide 3-kinase and nuclear factor-kappaB blocked the effects of SP on RANKL expression in periodontal ligament cells.
These results suggest that SP stimulates osteoclastic differentiation by increasing the expression of RANKL vs. OPG via the HO-1 pathway in periodontal ligament cells. The HO-1 pathway may be an effective therapeutic target for inhibiting chronic periodontitis involving alveolar bone resorption.
Journal of Periodontal Research 03/2010; 45(3):367-74. · 1.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: In a candidate gene association study, we found that the variations of calcitonin receptor (CALCR) gene were related to the risk of vertebral fracture and increased bone mineral density (BMD).
Calcitonins through calcitonin receptors inhibit osteoclast-mediated bone resorption and modulate calcium ion excretion by the kidney and also prevent vertebral bone loss in early menopause.
To identify genetically susceptible factors of osteoporosis, we discovered the variations in CALCR gene, genotyped in Korean postmenopausal women (n = 729), and examined the potential involvement of seven single-nucleotide polymorphism (SNPs) and their haplotypes in linkage disequilibrium block (BL_hts).
The SNPs, +43147G > C (intron 7), +60644C > T (exon13, 3' untranslated region), and their haplotypes, BL2_ht1 and BL2_ht2, showed a significant association with risk of vertebral fracture (p = 0.048-0.004) and BL2_ht1 showed a highly significant protective effect. Moreover, the polymorphism +60644C > T showed a highly significant association with BMD at both lumbar spine and femoral neck. The subjects carrying CC and CT genotypes with the SNP, +60644C > T, had higher BMD values at the lumbar spine (p = 0.01-0.001) and femoral neck (p = 0.025-0.009).
These results indicate that the CALCR gene may regulate bone metabolism, and +60644C > T in the CALCR gene may genetically modulate bone phenotype.
Osteoporosis International 11/2009; 21(8):1351-60. · 4.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are widely performed. Indications for these procedures have been extended in Korea and Japan. The aim was to evaluate whether these extended indications are safe.
All patients who had surgery for early gastric cancer at Seoul National University Bundang Hospital between May 2003 and December 2007 were identified from a prospective database. Lymph node status was examined in patients who met extended indications for EMR and had undergone surgical resection.
Of patients with mucosal cancers, 129 met extended indications for EMR or ESD and three (2.3 per cent) had lymph node metastasis. Of the 52 submucosal cancers meeting extended indications for EMR or ESD, two (4 per cent) had lymph node metastasis. Differentiated mucosal cancers without ulcer formation did not have lymph node metastasis, irrespective of size.
Extending the indications for EMR and ESD according to the Japanese Gastric Cancer Association guidelines carries an increased risk of lymph node metastasis. For cancers meeting these criteria, treatment by gastric resection with lymph node dissection should still be considered. A well differentiated mucosal cancer of any size without ulceration may be considered as an extended indication for EMR or ESD.
British Journal of Surgery 09/2009; 96(10):1157-61. · 4.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fluorine-free SmFeAsO1−x single crystals of a nominal composition with x = 0.15 were grown under the pressure of 3.3 GPa and at 1350–1450 °C by using the self-flux method. Plate-shaped crystals of a few–200 µm in lateral size were obtained. The resistively determined superconducting transition of a single crystal was at about 53.5 K, with a narrow resistive transition width of 0.5 K. The detailed crystal structure was analyzed by using synchrotron-irradiated x-ray diffractometry and high-resolution scanning transmission electron microscopy. A sharp transition, a low residual resistivity, and a large residual resistivity ratio indicate the high quality of our single crystals. The temperature and magnetic field dependences of the magnetization also confirmed the absence of extrinsic impurity phases.
Superconductor Science and Technology 06/2009; 22(7):075023. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pulmonary hypertension (PH) can occur during exercise and has an adverse effect on functional status, exercise tolerance and prognosis. However, the role of cardiac function abnormalities on exercise-induced PH in patients with normal left ventricular ejection fraction (LVEF) is unclear.
To analyse exercise-induced PH determinants in patients with normal LVEF.
396 subjects (160 male, mean age 55 (SD 13)) referred for exercise echocardiography underwent a graded, symptom-limited, supine bicycle exercise with two-dimensional and Doppler echocardiography. Tricuspid regurgitation (TR) velocity was measured at rest and during exercise. Pulmonary artery systolic pressure (PASP) was estimated from TR velocity by adding a right atrial pressure of 10 mm Hg. Patients were classified according to exercise induced PH, defined as present if PASP >50 mm Hg at 50 W of exercise. 135 patients (34%) had PASP >50 mm Hg during exercise. Patients with exercise-induced PH were older, more commonly female and had shorter exercise duration; however, LVEF was significantly higher. The systolic blood pressure at rest and during exercise was significantly higher in patients with exercise-induced PH (rest, 125 (18) vs 132 (18) mm Hg, p = 0.0003; 25 W, 146 (21) vs 157 (21) mm Hg, p<0.0001; 50 W, 157 (24) vs 170 (22) mm Hg, p<0.0001; 75 W, 168 (23) vs 183 (22) mm Hg, p<0.0001). Despite similar resting oxygen saturation, exercise oxygen saturation was significantly lower in subjects with exercise-induced PH than in those without. Numerous echocardiographic variables were significantly different between groups. In multivariate analysis, resting TR velocity (p<0.0001), E/E' (p = 0.027), age and gender were the strongest predictors of PASP during exercise.
Exercise-induced PH is common even in subjects with normal LVEF. It is strongly associated with E/E' ratio, TR velocity, age, systolic blood pressure during exercise and gender.
[show abstract][hide abstract] ABSTRACT: Reduction or disruption of the blood supply to the bone is involved in the pathogenesis of osteonecrosis of the femoral head (ONFH). An altered lipid metabolism is one of the major risk factors for ONFH. Sterol regulatory element binding protein, SREBF1 activates genes regulating lipid biosynthesis. The aim of this study was to examine the association between the polymorphisms of the SREBF1 gene and ONFH susceptibility in the Korean population. The SREBF1 gene in 24 unrelated Korean individuals was sequenced and two polymorphisms were detected. Two variants, IVS6 - 48 C > T and IVS7 + 117 A > G, were genotyped in 423 ONFH patients and 348 controls. The genotype frequency of IVS7 + 117 A > G in ONFH patients was significantly different from that of the control group with P value < 0.0001 (Adjusted OR; 6.88, 95% CI; 3.74-12.67). Moreover, the IVS7 + 117 A > G genotype showed an association with men, and further analysis stratified by etiological factors indicated that the genotype data was significantly associated with a high risk for patients with alcohol-induced ONFH (P < 0.0001). We found that the IVS7 + 117 A > G polymorphism of the SREBF1 gene is associated with an increased risk of ONFH in the Korean population.
Annals of Human Genetics 12/2008; 73(1):34-41. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: To understand patients' perceptions of clinical trials (CTs) is the principal step in the enrollment of patients to CTs. However, these perceptions in eastern countries are very rare. From 12 February 2007 to 13 April 2007, we consecutively distributed the questionnaire to 842 cancer patients who initiated a first cycle of chemotherapy regardless of each treatment step in the Seoul National University Hospital. Younger age, higher educational degree, higher economic status, and possession of private cancer insurance were related with significantly higher awareness of CTs (P=0.001, P=0.006, P=0.002, and P=0.009, respectively). However, unlike awareness, perceptions on benefits of CTs were not changed according to age, educational degree, and economic status (P=0.709, P=0.920, and P=0.847, respectively). Willingness was also not changed according to age, educational degree, economic status, and private cancer insurance (P=0.381, P=0.775, P=0.887, and P=0.392, respectively). Instead, males and heavily treated patients had more positive perceptions on benefits (P=0.002 and P=0.001, respectively) and more willingness to participate in CTs (OR=1.17, 1.14-2.75: OR=1.59, 1.01-2.51, respectively). In summary, cancer patients' awareness of CTs, perceptions on the benefit in CTs, and willingness to participate are differently influenced by diverse medical and social conditions. This information would be very helpful for investigators to properly conduct CTs in eastern cancer patients.
British Journal of Cancer 12/2008; 99(10):1593-9. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: The expression of heme oxygenase-1 (HO-1), stress-related enzyme, is induced in leukaemia and some cancer tissues, but relatively little is known about the differential pattern of HO-1 expression and proliferation in premalignant lesions of the epithelial oral mucosa. The purpose of this study was to evaluate whether HO-1 expression and proliferation were increased in preneoplastic lesions compared to normal and oral cancer tissues. Immunohistochemical staining was used to examine the expression patterns of HO-1 and proliferating cell nuclear antigen (PCNA) in a series of normal mucosa and mild-to-severe cases of oral epithelial dysplasia (OED) and oral squamous cell carcinoma. Both HO-1 and PCNA are expressed in the basal cells of normal oral mucosa. In patients with OED and carcinoma in situ, immunostaining for PCNA and HO-1 was more intense, and gradually extended into the superficial layers of the mucosa. HO-1 and PCNA expression was correlated with the degree of epithelial dysplasia. Oral squamous cell carcinoma also showed elevated expression of HO-1, but this level was not higher than in severe OED or carcinoma in situ. These results suggest that the up-regulation of HO-1 in premalignant oral lesions is part of an early cytoprotection mechanism against carcinogenesis in the oral mucosa.
International Journal of Oral and Maxillofacial Surgery 04/2008; 37(3):287-92. · 1.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Weight gain can be an adverse effect of antipsychotics that significantly affects long-term health and treatment compliance. Many reports have suggested that the 5-HT2C receptor gene (HTR2C) is related to appetite and eating behaviours associated with body weight change. We hypothesized that there was a relationship between the HTR2C -759C/T polymorphism and olanzapine-induced weight gain.
Seventy-nine Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long-term treatment for at least 3 months. We controlled the use of drugs other than olanzapine except benzodiazepines and anticholinergics. Genotyping for the HTR2C -759C/T polymorphism was performed on all participants.
We found that long-term treatment with olanzapine resulted in mean gains in weight and BMI of 5.2 kg and 1.93 kg/m(2), respectively. However, body weight changes from baseline to the study endpoint were not significantly associated with genotypes. The frequency of the T allele did not differ significantly between subjects with weight gains below and above a clinically significant cutoff, defined as 7% relative to baseline (chi(2) = 0.213, P = 0.445), indicating that the T allele had no protective effect against olanzapine-induced weight gain.
The findings from this study do not support the presence of a relationship between the -759C/T polymorphism of the HTR2C gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment.
Journal of Clinical Pharmacy and Therapeutics 03/2008; 33(1):55-60. · 2.10 Impact Factor
[show abstract][hide abstract] ABSTRACT: Microsatellite markers are an essential tool for genetic linkage analysis because of their high polymorphism content. Four hundred commercially available markers covering the entire genome were genotyped from 578 sib individuals from 249 Korean families. Allelic frequencies and heterozygosities were determined for each marker loci and compared between Korean, Taiwanese, Japanese and Caucasian populations. In the three Asian populations, 10-13% of the markers had less than 0.6 heterozygosity, whereas in the Caucasian population, only 0.5% of the markers had less than 0.6 heterozygosity. Mean identical by descent (IBD) values were calculated for 578 sib individuals. Analysis of IBD values greater than 0.5 suggested that markers with low heterozygosity can also provide positive linkages, at least for the IBD sharing method of model-free linkage analysis. The data presented in this study will be a useful reference for genome-wide screens of Koreans and comparative studies with other ethnic populations.
Journal of Human Genetics 02/2008; 53(3):254-66. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: The carcinoembryonic antigen (CEAs) family consists of a large group of evolutionarily and structurally divergent glycoproteins. The transforming growth factor-beta (TGF-beta) signaling pathway has been implicated in the stimulation of CEA secretion in TGF-beta-sensitive colon cells, thereby possibly modulating cell adhesion and differentiation. However, the specific CEAs targeted by TGF-beta signaling or underlying mechanism of the expression of CEAs has not yet been clarified. In this study, we investigated the specific CEAs targeted by the TGF-beta signaling pathway. In nine human gastric cancer cell lines examined, TGF-beta-responsive cell lines showed positive expression of CEAs. Expression patterns of CEA proteins correlated well with the level of CEA (CEACAM5) and CEACAM6 transcripts in these cell lines, but CEACAM1 expression was not observed in all of these cells. To investigate the role of TGF-beta signaling in CEA expression, we selected two TGF-beta unresponsive gastric cancer cell lines; SNU638 cells that contain a mutation in the TGF-beta type II receptor and SNU484 cells that express low to undetectable level of the TGF-beta pathway intermediate protein, Smad3. Restoration of TGF-beta signaling in these cells induced expression of the CEAs and increased activity of both CEA (CEACAM5) and CEACAM6 promoters. CEA expression was observed in the epithelium of the stomach of wild-type mice, but was markedly decreased in Smad3 null mice. These findings suggest that CEA (CEACAM5) and CEACAM6 are major target genes for Smad3-mediated TGF-beta signaling.
[show abstract][hide abstract] ABSTRACT: Although substance P (SP), a potent proinflammatory peptide, is involved in inflammation and immune responses, the effect of SP on the expression of macrophage inflammatory protein 3alpha[MIP-3alpha, chemokine C-C ligand 20 (CCL20)] in periodontal ligament (PDL) cells is unknown. Equally enigmatic is the link between SP, the stress protein heme oxygenase-1 (HO-1), and CCL20 production. We investigated whether SP induces the release of chemokine CCL20 from immortalized PDL (IPDL) cells, and further clarify SP-mediated pathways. We also examined the relationship between HO-1 and CCL20 by treating PDL cells with SP. Incubating IPDL cells with SP increased expression of CCL20 mRNA and CCL20 protein in a dose-time-dependent manner. Highly selective p38 and extracellular-regulated kinase 1/2 (ERK1/2) inhibitors abrogated SP-induced expression of CCL20 in IPDL cells. SP is also responsible for initiating phosphorylation of IkappaB, degradation of IkappaB and activation of nuclear factor (NF)-kappaB. SP induced expression of HO-1 in both a concentration- and time-dependent manner, and CCL20 reflected similar patterns. The inductive effects of SP on HO-1 and CCL20 were enhanced by HO-1 inducer hemin and the membrane-permeable guanosine 3',5'-monophosphate (cGMP) analogue 8-bromo-cGMP. Conversely, this pathway was inhibited by the HO-1 inhibitor zinc protoporphyrin IX (ZnPP IX) and the selective inhibitor of guanylate cyclase, 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one (ODQ). We report herein the pathway that connects SP along with other modulators of neuroimmunoregulation to the induction of HO-1 and the inflammatory mediator macrophage inflammatory protein (MIP)-3alpha/CCL20 in IPDL cells, which play an important role in the development of periodontitis or inflammation during orthodontic tooth movement.
[show abstract][hide abstract] ABSTRACT: Although induction of heme oxygenase-1 by H2O2 has been reported, the protective role of heme oxygenase-1 against the cytotoxic and osteoclastogenic effects of H2O2 have not been elucidated in human periodontal ligament cells. The aim of this work was to investigate the defense mechanism of heme oxygenase-1 on H2O2-induced cytotoxicity and to analyze the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin as markers for osteoclast differentiation in periodontal ligament cells.
Using human periodontal ligament cells, cytotoxicity was measured by the 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT) assay, and expression of heme oxygenase-1, RANKL, and osteoprotegerin mRNA was determined by reverse transcription-polymerase chain reaction.
H2O2 produced a cytotoxic effect by reducing the cell viability and enhancing the expression of heme oxygenase-1 and RANKL mRNAs in a concentration- and time-dependent manner. Additional experiments revealed that heme oxygenase-1 inducer (hemin), a membrane-permeable cGMP analog (8-bromo-cGMP), carbon monoxide, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase inhibitor, protein kinase inhibitor (KT5823), and nuclear factor-kappaB inhibitor (pyrrolidine dithiocarbamate) also blocked the effects of H2O2 on cell viability and RANKL mRNA expression in periodontal ligament cells.
These data suggest that heme oxygenase-1 induction plays a protective role in periodontal ligament cells against the cytotoxic and RANKL-inducing effects of H2O2, through multiple signaling pathways.
Journal of Periodontal Research 09/2007; 42(4):331-9. · 1.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Serum response factor (SRF) is a widely expressed transcription factor involved in immediate-early and tissue-specific gene expression, cell proliferation and differentiation. We defined a new role of SRF as a nuclear repressor of the tumor growth factor β1 (TGF-β1) growth-inhibitory signal during cell proliferation. We show that SRF significantly inhibits the TGF-β1/Smad-dependent transcription by associating with Smad3. SRF causes resistance to the TGF-β1 cytostatic response by directly repressing the Smad transcriptional activity and Smad binding to DNA. Furthermore, we demonstrated that overexpression of SRF markedly decreases the level of Smad3 complex binding to the promoters of Smad3 target genes, p15INK4b and p21Cip1. This leads to the inhibition of expression of TGF-β1-responsive genes. SRF therefore acts as a nuclear repressor of Smad3-mediated TGF-β1 signaling.