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Biomedical subjects

Hiroyuki Kato

Publications and source records attributed to Hiroyuki Kato.

At least 37 records · Page 2Linked to original sources
PubMed2005

Correlation between laminin-5 gamma2 chain and epidermal growth factor receptor expression in esophageal squamous cell carcinomas.

OBJECTIVES: Laminin-5 gamma2 chain (LN-5 gamma2) is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. We evaluated the association of LN-5 gamma2 and epidermal growth factor receptor (EGFR) expression in esophageal squamous cell carcinoma (SCC). METHODS: LN-5 gamma2 and EGFR expression was evaluated in 110 esophageal SCC patients by immunohistochemistry, and was confirmed using esophageal SCC cell lines by Western blot analysis. RESULTS: LN-5 gamma2 expression in the invasive front of the tumor was correlated with the depth of invasion (p = 0.0001), lymph node metastasis (p = 0.0011) and pathological stage (p = 0.0001). The strong expression of EGFR was also correlated with lymph node metastasis (p = 0.0456) and the pathological stage (p = 0.0055). In patient survival, LN-5 gamma2 positivity and/or strong EGFR expression showed a significantly low survival rate as compared with those with lesser expression of LN-5 gamma2 and EGFR. Immunohistochemically, LN-5 gamma2 expression was significantly correlated with EGFR expression (p < 0.0001). Western blot analysis also confirmed the correlated expression of LN-5 gamma2 and EGFR in SCC cell lines except 2 of the 5 cell lines. CONCLUSIONS: This study suggests that coexpression of LN-5 gamma2 and EGFR is closely related to the progression and poor prognosis of esophageal SCC.

Aged↗
PubMed2005

Differential sensitivity of paclitaxel-induced apoptosis in human esophageal squamous cell carcinoma cell lines.

PURPOSE: Paclitaxel is a highly effective chemotherapy agent against adenocarcinomas and squamous cell carcinomas of the esophagus. However, its precise effects in human esophageal cancer cells are not well understood. This study was designed to examine the relationship between cell-cycle phases of paclitaxel-activated checkpoints and to elucidate the molecular pathway of the effect of paclitaxel in human esophageal squamous cell carcinoma (ESCC) cell lines. METHODS: The three human ESCC cell lines--TE-2, TE-13 and TE-14--were examined for their response to paclitaxel. ESCC cells were treated with various concentrations of paclitaxel for 1-3 days using MTT assay. The cell-cycle progression and apoptosis were examined by flow cytometry. DNA fragmentation assay was carried out to confirm the fragmented cells as hallmark for apoptotic cells. In additional, the expression of apoptosis-related proteins in ESCC-treated cells was then examined by Western blot analysis. RESULTS: TE-14 cells demonstrated the highest sensitivity among all cells. G2/M cell-cycle arrest occurs prior to paclitaxel-induced apoptosis in ESCC cells. The fragmentation of chromatin was observed in drug treated TE-13 and TE-14 cells by flow cytometry and DNA ladder formation. In contrast, the measurement for TE-2 cells was more suggestive of phenotype a resistant in response to paclitaxel treatment. Western blot analysis results showed that the mitochondrial pathway might be involved in paclitaxel-induced apoptosis in ESCC cell lines. CONCLUSION: Differential sensitivity was observed in human ESCC cell lines in response to paclitaxel treatment. G2/M arrest occurs with a prior to paclitaxel-induced apoptosis and might be mediated by the mitochondrial (intrinsic) apoptosis pathway in human ESCC cells.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells.

Chronic infection with cagA-positive Helicobacter pylori is associated with the development of atrophic gastritis, peptic ulcers, and gastric adenocarcinoma. The cagA gene product CagA is injected into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Translocated CagA disturbs cellular functions by physically interacting with and deregulating intracellular signaling transducers through both tyrosine phosphorylation-dependent and -independent mechanisms. To gain further insights into the pathophysiological activities of CagA in gastric epithelial cells, we executed a genome-wide screening of CagA-responsive genes by using DNA microarray and identified nuclear factor of activated T cells (NFAT) transcription factors whose binding sites were overrepresented in the promoter regions of CagA-activated genes. Results of reporter assays confirmed that CagA was capable of activating NFAT in a manner independent of CagA phosphorylation. Expression of CagA in gastric epithelial cells provoked translocation of NFATc3, a member of the NFAT family, from the cytoplasm to the nucleus and activated an NFAT-regulated gene, p21WAF1/Cip1. CagA-mediated NFAT activation was abolished by inhibiting calcineurin or phospholipase Cgamma activity. Furthermore, treatment of cells with H. pylori VacA (vacuolating toxin), which inhibits NFAT activity in T lymphocytes, counteracted the ability of CagA to activate NFAT in gastric epithelial cells. These findings indicate that the two major H. pylori virulence factors inversely control NFAT activity. Considering the pleiotropic roles of NFAT in cell growth and differentiation, deregulation of NFAT, either positively or negatively, depending on the relative exposure of cells to CagA and VacA, may contribute to the various disease outcomes caused by H. pylori infection.

Antigens, Bacterial↗
PubMed2005

Expression of RCAS1 in esophageal squamous cell carcinoma is associated with a poor prognosis.

BACKGROUND: Receptor-binding cancer antigen expressed on SiSO cells (RCAS1) has been reported to act as a ligand for a receptor present on normal peripheral lymphocytes and to induce apoptotic cell death. We aimed to elucidate the significance of RCAS1 expression in human esophageal squamous cell carcinomas (ESCC). METHODS: RCAS1 expression was examined immunohistochemically in surgically resected esophageal carcinoma tissues from 114 patients. We also examined the relationships between RCAS1 expressions, the tumor Ki-67 indices (a marker of proliferation), and the number of CD8+ tumor-infiltrating lymphocytes (TILs). RESULTS: RCAS1 immunoreactivity was detected in the membranes and cytoplasm of the tumor cells. Of the 114 esophageal carcinomas, 39 (34.2%) were strongly positive for RCAS1 immunostaining on the membranes of the cancer cells, 41 (36.0%) were weakly positive, and 34 (29.8%) were negative. A comparison of RCAS1 expression and clinicopathological characteristics in all 114 patients revealed significant associations between RCAS1 expression and lymph node status (P < 0.05), and pathologic stage (P < 0.05). The survival rates of patients with RCAS1-negative tumors were significantly higher than those of patients with both RCAS1-weak positive tumors and RCAS1-strong positive ones (log-rank P < 0.05). Multivariate analysis revealed that RCAS1 positivity was an independent prognostic factor (P < 0.05). The relationship between RCAS1 expression and the numbers of CD8+ T-cells in the primary tumors revealed that RCAS1-negative tumors tended to contain more of these cells than both RCAS1-weak positive tumors and RCAS1-strong positive ones (P = 0.2495). CONCLUSIONS: RCAS1 may play a significant role in tumor progression via an immune escape mechanism; thus, RCAS1 expression could be used as a predictor of poor prognosis in patients with ESCC.

Adult↗
PubMed2005

The incremental effect of positron emission tomography on diagnostic accuracy in the initial staging of esophageal carcinoma.

BACKGROUND: The purpose of the current study was to assess whether [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) provides incremental value (e.g., additional information on lymph node involvement or the presence of distant metastases) compared with computed tomography (CT) in patients with esophageal carcinoma. METHODS: The authors examined 149 consecutive patients with thoracic esophageal carcinoma. Eighty-one patients underwent radical esophagectomy without pretreatment, 17 received chemoradiotherapy followed by surgery, 3 underwent endoscopic mucosal resection, and the remaining 48 patients received definitive radiotherapy and chemotherapy. The diagnostic accuracy of FDG-PET and CT was evaluated at the time of diagnosis. RESULTS: The primary tumor was visualized using FDG-PET in 119 (80%) of 149 patients. Regarding lymph node metastases, FDG-PET had 32% sensitivity, 99% specificity, and 93% accuracy for individual lymph node group evaluation and 55% sensitivity, 90% specificity, and 72% accuracy for lymph node staging evaluation. PET exhibited incremental value over CT with regard to lymph node status in 14 of 98 patients who received surgery: 6 patients with negative CT findings were eventually shown to have lymph node metastases (i.e., they had positive PET findings and a positive reference standard [RS]); 6 patients with positive CT findings were shown not to have lymph node metastases (i.e., they had negative PET findings and a negative RS); and 2 patients were shown to have cervical lymph node metastases in addition to mediastinal or abdominal lymph node metastases. Among the remaining patients, PET showed incremental value over CT with regard to distant organ metastases in six patients. The overall incremental value of PET compared with CT with regard to staging accuracy was 14% (20 of 149 patients). CONCLUSIONS: FDG-PET provided incremental value over CT in the initial staging of esophageal carcinoma. At present, combined PET-CT may be the most effective method available for the preoperative staging of esophageal tumors.

Adult↗
PubMed2005

Genetic alterations in esophageal cancer.

Esophageal cancer is a common malignancy with a striking variation in geographical distribution; a reflection of exposure to specific environmental factors, which are still poorly defined. We discuss the recent progress made in the investigation of the molecular biology of esophageal cancer, addressing the topics of genetic alterations, methylation, overexpression of molecules thought to cause malignant transformation, carcinogenesis, invasion, and metastasis. We review six aspects of the research literature on esophageal cancer: epidemiology and etiology, epidermal growth factor receptor and related growth factor receptors, cell cycle regulatory proteins, transforming growth factor-beta/Smad proteins, mismatch repair genes, and other genes. This article provides a conceptual basis for evaluating studies on the molecular mechanism of esophageal carcinogenesis and for devising therapeutic and preventive strategies based on molecular biology. We hope that in the near future, the clinical outcome of patients with esophageal carcinoma will be improved by a better understanding of the basic mechanisms of carcinogenesis.

Carcinoma, Squamous Cell↗
PubMed2005

Effects of chronic administration with nilvadipine against immunohistochemical changes related to aging in the mouse hippocampus.

We investigated the effect of Ca2+ antagonist nilvadipine on age-related immunohistochemical alterations in ubiquitin and S100beta protein of the hippocampal CA1 sector in mice using 8-, 18-, 40-, and 59-week-old mice. No significant changes in the number of neuronal cells were observed in the hippocampal CA1 sector up to 59 weeks after birth. The administration of nilvadipine did not affect the number of the hippocampal CA1 cells of 40-week-old mice. Age-dependent increases in ubiquitin immunoreactivity were observed in the hippocampal CA1 neurons up to 59 weeks after birth. The administration of nilvadipine prevented dose-dependently the increases in the number of ubiquitin-immunoreactive neurons in the hippocampal CA1 sector of 40-week-old mice. S100,beta immunoreactivity was unchanged in the hippocampal CA1 sector up to 40 weeks after birth. In 59-week-old mice, the level of staining of S100beta-immunoreactive cells increased significantly in the hippocampal CA1 sector. The administration of nilvadipine decreased dose-dependently the number of S 100beta-immunoreactive cells in the hippocampal CA1 sector of 40-week-old mice. The present study demonstrates that age-related increases in ubiquitin system may play a pivotal role in protecting neuronal cell damage during aging. In contrast, our results suggest that expression of S 100beta protein in the hippocampal CA1 sector may play an exacerbating factor in some neuronal cells damaged by aging. Our results also demonstrate that nilvadipine, a dihydropyridine-type calcium channel blocker, can prevent dose-dependently the increases in the ubiquitin immunoreactive neurons and decrease the number of S100beta immunoreactive cells in the hippocampal CA1 neurons of aged mice. These results suggest that nilvadipine may offer a new approach for the treatment of neuronal dysfunction in aged humans.

Aging↗
PubMed2005

Effect of angiotensin-converting enzyme inhibitor perindopril on interneurons in MPTP-treated mice.

We examined the effects of perindopril on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP at 1-h intervals. Administration of perindopril showed dose-dependent neuroprotective effects against striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 3 days after MPTP treatment. Our immunohistochemical study showed that MPTP can severe damage in tyrosine hydroxylase (TH)-immunoreactive neurons after MPTP treatment. The administration of perindopril significantly attenuated MPTP-induced substantia nigra and striatal damage. The present study also showed that the immunoreactivity of parvalbumin (PV)- or neuronal nitric oxide synthase (nNOS)-positive cells in the substantia nigra was decreased 7 days after MPTP treatment, whereas no significant changes were observed in these cells of the striatum throughout the experiments. The administration of perindopril significantly attenuated MPTP-induced decrease of the PV- or nNOS-immunoreactivity in the nigral cells. In double-labeled immunostaining with anti-PV and anti-nNOS antibody, PV-immunoreactive cell bodies and fibers were not double-labeled for nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra after MPTP treatment. Furthermore, PV- or nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra were not double-labeled for TH-immunoreactive cell bodies and fibers. These results demonstrate that the ACE inhibitor perindopril has a dose-dependent protective effect against MPTP-induced striatal dopamine, DOPAC and HVA depletion in mice. The present study also demonstrates that perindopril is effective against MPTP-induced degeneration of the nigral neurons and interneurons. Furthermore, our immunohistochemical study suggests that PV-immunoreactive cells and nNOS-immunoreactive cells are different interneurons in both the striatum and substantia nigra. Thus, our results provide further evidence that the ACE inhibitor perindopril may offer a novel therapeutic strategy for Parkinson's disease (PD).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin.

We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can prevent the damage of interneurons in the hippocampus after cerebral ischemia. Thus, our study provides valuable information for the pathogenesis after cerebral ischemia.

Animals↗
PubMed2005

Cooperation of ER-60 and BiP in the oxidative refolding of denatured proteins in vitro.

ER-60 is a PDI family protein that has protein thiol-disulfide oxidoreductase activity. It has been shown to associate with BiP in the endoplasmic reticulum. Here, we analyzed the cooperation of ER-60 and BiP in the oxidative refolding of denatured proteins in vitro. ER-60 facilitated the refolding of 20 or 30% of denatured alpha-lactalbumin or ribonuclease B during incubation for 80 min, and these levels of nearly doubled on the addition of BiP to the reaction mixture. BiP alone could not refold denatured ribonuclease B, but could refold denatured alpha-lactalbumin a little. Enhancement of oxidative refolding of alpha-lactalbumin by ER-60 could be detected only when ER-60 was present from the start of refolding. On surface plasmon resonance analysis, ER-60 was shown to associate with BiP. The association was not influenced by ATP or ADP. Domains a and/or b' of ER-60 were implicated in the association with BiP.

Endoplasmic Reticulum Chaperone BiP↗
PubMed2005

Radial osteotomies for teenage patients with Kienböck disease.

Age seems to affect the efficacy of radial osteotomies for Kienböck disease. We questioned whether an osteotomy would produce acceptable results in teenagers. We retrospectively identified 11 patients (six males and five females) between 11-19 years of age who were treated with radial osteotomies for Kienböck disease. Preoperatively, three patients had Lichtman Stage II disease, two patients had Stage IIIA disease, and six patients had Stage IIIB disease. Two patients with zero or positive ulnar variance had lateral closing wedge osteotomies, and nine patients with negative ulnar variance had radial shortenings. All patients were evaluated clinically and radiographically. At a mean followup of 50 months, 10 of 11 patients were free from pain, and the remaining one patient had moderate wrist pain during strenuous activity. All patients except one, who had Stage IIIB disease, had an excellent clinical outcome. Radiographic improvement, indicating lunate revascularization, was seen for eight patients. Despite Stage IIIB disease, radial osteotomies produced excellent clinical results in five of six teenage patients. The current results indicate that radial osteotomies are effective in improving not only short-term clinical outcomes, but also radiographic findings in teenage patients with Kienböck disease.

Adolescent↗
PubMed2005

Physiolysis for correction of the delta phalanx in clinodactyly of the bilateral little fingers.

We report the results of long-term follow-up after Vickers' physiolysis of the trapezoidal delta phalanx in a boy aged five year and six months with bilateral clinodactyly of the little finger. Radial deviation of the little finger was corrected from 36 degrees to 15 degrees on the left, and from 35 degrees to 15 degrees on the right at last follow-up six years and five months after surgery. The patient's parents were satisfied with the cosmetic appearance. X-ray film showed the abnormal distal epiphyses of the middle phalanges of the little fingers had disappeared.

Adipose Tissue↗
PubMed2005

Treatments of osteoarthritis of the distal radioulnar joint: long-term results of three procedures.

Sixty-one wrists in 61 patients with osteoarthritis of the distal radioulnar joint treated by three consecutive procedures (20 Darrach, 25 Sauvé-Kapandji and 16 hemiresection-interposition arthroplastic procedures) were retrospectively evaluated. We preferred to perform Darrach's procedure in even the early stages of osteoarthritis of the distal radioulnar joint prior to introduction of Sauvé-Kapandji and hemirestion-interposition arthroplastic procedures. Subsequently the hemirestion-interposition arthroplasty was indicated when the triangular fibrocartilage cartilage was intact or could be reconstructed and the Sauvé-Kapandji when the triangular fibrocartilage complex could not be reconstructed or there was positive ulnar variance of more than 5 mm even though the triangular fibrocartilage complex was functional. Patient's age at operation averaged 59.8 years. There were 36 men and 25 women. There were 38 primary and 23 secondary osteoarthritis cases. Post-operative pain, range of motion, grip strength, return to work status; and radiographic results were evaluated. At the five- to 14-year (average, ten years) follow-up evaluation, relief of pain from Darrach procedure was inferior to the Sauvé-Kapandji procedure and hemiresection-interposition arthroplasty although this was not statistically significant. After both the Sauvé-Kapandji procedure and hemiresection-inteposition arthroplasty, post-operative improvements in flexion and extension of the wrist had statistical significance. Post-operative improvements in pronation and supination of the forearm showed statistical significances after all procedures. Improvements of post-operative grip strength and return to an original job in the Sauvé-Kapandji procedure and hemiresection-interposition arthroplasty were statistically superior to those with a Darrach's procedure. There were many post-operative complications following the Darrach's procedure. Darrach's procedure is better indicated for severe osteoarthritic changes of the distal radioulnar joint in elderly patients. We believe the operative indications between the Sauvé-Kapandji procedure and hemiresection-interposition arthroplasty are best determined prior to surgery by the existence and status of the triangular fibrocartilage complex and the amount of the positive ulnar variance.

Aged↗
PubMed2005

Successful long-term treatment with once-daily injection of low-dose octreotide in an aged patient with insulinoma.

The patient was an 83-year-old woman who was admitted to our hospital for evaluation and treatment of chronic hypoglycemia that was first identified 3 years earlier. Serum insulin and C-peptide levels were both elevated during hypoglycemia. Contrast abdominal computed tomography revealed a tumor in the body of the pancreas with blushing during the early phase, and insulinoma was diagnosed. The patient declined surgery because of advanced age, so treatment was started with octreotide, a somatostatin analogue. Hypoglycemia has been successfully controlled with low-dose, once-daily octreotide over 33 months. Few reports have described long-term octreotide administration for benign insulinoma. Moreover, this case is interesting from the perspective of hypoglycemic control using only low-dose, once-daily octreotide. Although somatostatin may induce hypoglycemia in insulinoma, treatment may be useful in patients who are not candidates for surgery, provided that careful monitoring is maintained.

Aged, 80 and over↗
PubMed2005

[Clinical outline of Barrett's esophagus].

Barrett's esophagus is one of the important gastrointestinal disease in Europe and the United States. It was recognized as not only complication of reflux esophagitis, but also pre-malignant lesion of adenocarcinoma. Recently, realization of Barrett's esophagus is attentioned in Japan, because increasing of reflux esophagitis for westernization of eating habit, living habit and aging of the population. In this section, we present general consideration and clinical research of Barrett's esophagus. We expect Barrett's esophagus will gradually increase near the future and need to research abundantly about controversial point of Barrett's esophagus. We also think it is important to accumulate intensively the clinical data of Barrett's esophagus patients.

Adenocarcinoma↗
PubMed2004

Arundic acid, an astrocyte-modulating agent, protects dopaminergic neurons against MPTP neurotoxicity in mice.

We examined the neuroprotective effects of a novel astrocyte-modulating agent, arundic acid (ONO-2506), in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Male C57BL/6 mice received four intraperitoneal injections of MPTP (20 mg/kg) at 2 h intervals. Dopamine content in the striatum was reduced to 21% of the normal control after 7 days. Treatment with arundic acid (30 mg/kg, i.p.) administered 1 min, 6 h, 24 h, 48 h, and 72 h after the last MPTP injection prevented the dopamine depletion (52% of the control, p<0.01). In addition, this treatment resulted in behavioral benefits. Behavioral testing showed that MPTP-injected mice exhibited motor deficits in the pole test and catalepsy test after 7 days, but arundic acid prevented the appearance of motor abnormalities in these tests. The MPTP-injected animals exhibited an 87% loss of tyrosine hydroxylase-containing dopaminergic neurons in the substantia nigra after 7 days, but the arundic acid-treated mice showed only a 56% reduction (p<0.01). GFAP-positive reactive astrocytes were accumulated in the striatum and substantia nigra 7 days after the MPTP injection, whereas arundic acid treatment induced an earlier appearance of reactive astrocytes by 3 days. The reactive astrocytes increased the production of S-100 protein, which is thought to promote neuronal damage, but arundic acid suppressed the expression of S-100. Thus, arundic acid protected dopaminergic neurons against MPTP neurotoxicity in mice and ameliorated neurological deficits. The results suggest that the neuroprotection is mediated through the modulation of astrocytic activation, including the inhibition of S-100 protein synthesis.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Histone deacetylase 7 associates with hypoxia-inducible factor 1alpha and increases transcriptional activity.

Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that controls expression of genes responsive to low oxygen tension, including vascular endothelial growth factor (VEGF), erythropoietin, and glycolytic enzymes. The activity of HIF-1alpha is regulated by binding to the transcriptional co-activator cAMP-response element-binding protein-binding protein (CBP)/p300. Using the yeast two-hybrid screening system, we found that the inhibitory domain of HIF-1alpha strongly interacted with the C-terminal domain of histone deacetylase (HDAC) 7. The o-nitrophenyl beta-d-galactopyranoside assay revealed that regions containing amino acids 735-785 of HIF-1alpha and amino acids 669-952 of HDAC7 were minimum contact sites of the interaction. The binding of HDAC7 with HIF-1alpha was reproduced in HEK293 cells grown under normoxic and hypoxic conditions (2% O(2)). HDAC7 bound solely to HIF-1alpha among other HIF-alpha family members, including HIF-2alpha and HIF-3alpha, whereas HIF-1alpha only interacted with HDAC7 in the class II HDAC family. Although HDAC7 was localized dominantly in the cytoplasm at normal oxygen concentrations, HDAC7 co-translocated to the nucleus with HIF-1alpha under hypoxic conditions. In the nucleus, HDAC7 increased transcriptional activity of HIF-1alpha through the formation of a complex with HIF-1alpha, HDAC7, and p300. Taken together, these results indicate that HDAC7 is a novel transcriptional activator of HIF-1alpha

Acetyltransferases↗