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고콜레스테롤혈증 성인환자에서 무증상 갑상선 기능저하증의 빈도와 혈청 콜레스테롤 치에 대한 혈청 TSH 의 영향
정원제(Won Jea Jeong),박병헌(Byeong Heon Park),박철영(Cheol Young Park),류미숙(Mee Sook Ryu),오승준(Seung Joon Oh),우정택(Jeong Tack Woo),김성운(Sung Woon Kim),양인명(In Myoung Yang),김진우(Jin Woo Kim),최영길(Young Kil Choi),팽정령( 대한내과학회 2002 대한내과학회지 Vol.62 No.2
N/A Background: Subclinical hypothyroidism is frequently discovered from hypercholesterolemic adults. It is defined as an asymptomatic state which characterized by normal free thyroxine (FT4) and elevated thyroid stimulating hormone (TSH) level. Hypercholesterolemia is a major risk factor for coronary heart disease, however hypercholesterolemia caused by hypothyroidism can be easily managed by thyroid hormone replacement. The screening of thyroid disease in hypercholesterolemia patient must be emphasized in order to find out correctable hypothyroidism. So we screened the prevalence of overt and subclinical hypothyroidism at different hypercholesterol levels in middle-aged men and women and also analyzed the correlation between TSH and total cholesterol level. Methods: We measured serum TSH levels and FT4 by radioimmunoassay from 491 patients with hypercholesterolemia. The subjects were divided into two groups according to serum cholesterol level. Group I was serum cholesterol ≥240 -〈300 mg/dL and group II was ≥300 mg/dL. Subclinical hypothyroidism was defined as TSH levels higher than 4 mU/L, in the presence of normal FT4 concentration. Results: The overall prevalence of subclinical and overt hypothyroidism was 3.4% and 2.5% in men and 4.7% and 3.5% in women of middle age. In men the prevalence of overt and subclinical hypothyroidism increased from 2.3% of group I to 16.1% in the group II (p<0.05). In women that increased from 5.2 % to 12.9 % (p<0.05). After age correction, an increase of 1 mU/L TSH in men was associated with an increase of 3.2 mg/dL total cholesterol (p<0.01). A similar trend was also found in women (2.1 mg/dL p=0.052). Conclusion: In this population, the prevalence of hypothyroidism is up to 16.1% in middle-aged men, 12.9% in middle-aged women with high total cholesterol and it may justify screening of thyroid disease in hypercholesterolemic patients especially in clinical practice.(Korean J Med 62:187-193, 2002)
GH3세포에서 세포내 cAMP에 의한 소마토스타틴 수용체 유전자 2의 전사단계에서의 발현증가
최영길,김영설,양인명,박승준,정주호,엄교숙,임성빈,정지창,고계창 대한내분비학회 1998 Endocrinology and metabolism Vol.13 No.1
Background: An earlier study demonstrated that pituitary tumors of good octreotide responders have high density of somatostatin receptor(SSTR). We previously reported that growth hormone (GH)-secreting pituitary tumors with Gas mutations show good response to octreotide. As Gas mutations constitutively increase intracellular cAMP, we therefore hypothesized that the mutations may induce high e~xpression of SSTR. As a pilot study for the hypothesis, we investigated whether SSTR gene expression is activated by intracellular cAMP. Methods: We examined SSTR2 mRNA expression by Northern blot assay and RT-PCR and in vitro transcription. Results: In Northern blot assay, we could not detect any mRNA even after 2 weeks in all the rat organs and the cell lines except AtT-2Q cells. However, by using RT-PCR and in vitro transcription, we could detect very small amount of the SSTR2 message. GH3 cells were stimulated with farskolin and isobutylmethylxanthine, cholera toxin, and GHRH for 2 hours. The expression of SSTR2 gene was increased remarkabiy, whereas B-actin gene expression was comparable. Conclusion: These pre data suggest that SSTR2 gene expression is transcriptionally activated by intracellular cAMP, supporting our hypothesis that Gas mutations induce high expression of SSTR to compensate the putative stimulation of somatotroph. The transfection assay using the vectors wbich express mutated Gas gene is in progress. (J Kor Soc Endocrinol 13:24-33, 1998)
쥐의 갑상선 자극호르몬-방출호르몬(TRH) 유전자의 Glucocorticoid 반응요소(Glucocorticoid REsponse Element, GRE) 의 특성
김진우,최영길,김영설,김성운,양인명,우정택,정운원 대한내분비학회 1999 Endocrinology and metabolism Vol.14 No.2
Background: We previously demonstrated that the promoter of rat TRH gene has GRE half site (TGTTCT) between -210 bp and -205 bp flanking with similar sequences of TPA response element (TRE), TAGTCA, at a distance of several base pairs from the GRE half site. It promps us to hypothesize that this composite GRE/TRE sequence can provide a site for interaction between glucocorticoid receptor (GR) and c-Jun. Thus, we investigated whether the composite sequence mediates transcriptional regulation induced by dexamethasone (DEX) and 12-O-tetradecanoyl phobol-13-acetate (TPA), and whether it binds GR and c-Jun. Methods: A luciferase expressing plasmids that contain a part of rat TRH promoter including the composite sequence or their mutants were transfected into HeLa cells by Fugene 6. After the cells were incubated overnight with DEX and TPA, the luciferase activity was measured in a chemiluminometer. A gel retardation assay was performed after binding of the labeled composite sequence or its mutants with GR and c-Jun. Results: DEX increased the transcriptional activity of the plasmid containing the wild type GRE by 2.5 folds, and TPA increased the transcriptional activity by 4 folds. The simultaneous stimulation with DEX and TPA synergistically increased the transcriptional activity by 10 folds. Two mutants whose GRE half sits were altered showed no responses to DEX, and suppressed the TPA-induced or both agents-induced transcriptional activity by 50%. Two mutants whose TRE-like sites were altered suppressed the DEX-induced transcriptional activity by 20%, TPA-induced trarptional activity by 25%, and both agents-induced transcriptional activity by 50%. Gel retardation assay showed that the composite sequence fonned a complex with GR and its mutants bound to GR with remarkably less affinity. c-Jun also bound to the composite sequence to form two cornplexes with less affinity compared to the AP-1 consensus sequence. The mutants of the TRE-like sequence bound to c-Jun with a significantly lower affinity compared to that of the wild type. Simulateous binding of the composite sequence with GR and c-Jun did not form any larger complex. The complex of GR and the composite sequence was much smaller than that formed by c-Jun, suggesting that GR binds to the composite sequence as a monomer. Conclusion: These results suggest that the composite sequence of GRE half site and TRE-like site on the promoter of rat TRH gene provides binding sites for GR and c-Jun, which mediate the interaction between two signal transduction pathways. (J Kor Soc Endocrinol 14:265-277, 1999)
성장호르몬 분비성 뇌하수체 선종에서 소마토스타틴 수용체 제2 아형및 제 5 아형 유전자 발현
김진우,최영길,김영설,김성운,양인명,우정택,박승준,김국기 대한내분비학회 1997 Endocrinology and metabolism Vol.12 No.4
Background: SSTR2 and SSTR5 are most frequently observed in GH-secreting pituitary tumors, and SSTR5 is believed to be more specific to mammosomatotroph lineage. Octreotide binds with high affinity to those two types. There is no report that investigates the quantitative comparison of the two subtype gene expressions, and the correlation between their gene expressions and GH response to octreotide in GH-secreting pituitary adenomas. Method: GH response to octreotide was examined in 8 acromegalic patients before transsphenoidal adenomectomy. Genomic DNA and RNA were prepared from fresh frozen tumor tissues. PCR was performed to amplify and sequence the region between codon 184 and 251 that includes exons 8 and 9 of the Gas gene. mRNAs of SSTR2 and SSTRS were quantitated by the comparative RT-PCR and in vitro transcription. Results: The in vitro transcripts of SSTR2 and SSTR5 cDNA were detected in all tumors. The amount of SSTR transcripts was considerably variable between the tumors. The amount of SSTR5 transcript was significantly smaller than that of SSTR2 transcript(0.07+-0.02 vs. 0.87+-0.10), and they did not show any correlation . There was no signicant difference in sex, age, tumor size and grade, basal GH levels, and the GH responses to octreotide between the group with high and low SSTR gene expression. No significant correlation was found between the GH response to octreotide and the amount of SSTR2 transcript, wherease the amount of SSTR5 transcripts showed a tendency of negative correlation with the octreotide response. Tumors with gsp oncogene showed signifi- cantly higher response to octreotide than those without the oncogene. The amount of SSTRS transcript in gsp-positive tumors was significantly smaller than in gsp-negative tumors (0.03+-0.01 vs. 0.12+-0.03). Conclusion: These results suggest that SSTRS gene expression is lower than that of SSTR2 in GH-secreting adenomas. It is probably attributed to the binding of somatostatin to SSTR5 which has a higher affinity to the hypothalamic somatostatin, Tumors with gsp-oncogene is likely to express a higher density of SSTR5 than those without the oncogene. (J Korean Soc Endocrinol 12:508-517, 1997)
Site-Directed Mutagenesis를 이용한 쥐 TRH 유전자의 당질코르티코이드 반응요소와 TPA 반응요소의 분석
김진우,최영길,김영설,김성운,양인명,우정택,정운원,최영길 대한내분비학회 1999 Endocrinology and metabolism Vol.14 No.2
Background: We previously demonstrated that a GRE/TRE composite sequence, which is located between 200 bp and 220 bp relative to the transcriptional start site of rat TRH gene, is responsible for the dexamethasone (DEX)- and TPA-induced transcriptional activation, and the transcriptional activation by DEX is mediated by interaction between glucocorticoid receptor (GR) and a TRE-binding transcriptional factor such as c-Jun. However, a non-specific binding with the transciption factors can not be excluded as the mutants used in the previous report could not inhibit the binding of GR and c-Jun completely, and it remains unclear which one of the two TRE-like sequences is critical for the interaction of the two transcription factors. Methods: Luciferase expressing plasmids that contain a part of rat TRH promoter including the composite GRE sequence or its mutants were transfected into HeLa cells by Fugene 6. After the cells were incubated overnight with DEX or/and TPA, the luciferase activity was measured in a chemiluminometer. A gel retardation assay was performed after binding of the labeled composite sequence or its mutants with GR and c-Jun. Results: DEX and TPA increased the transcriptional activity of the wild type composite sequence by 3 folds and 4 folds, respectively, and the combined stimulation increased the activity by 10 folds. The mutants of which all 6 nucleotides of the GRE half site were replaced and removed almost did not bind to GR and eould not enhance the transcriptional activity at all in response to DEX. The GRE-deleted mutant bound to c-Jun with a remarkably lower affinity and showed a lower response to TPA, whereas the GRE-replaced mutant bound to c-Jun with a similar affinity and showed a similar response to TPA compared to those of the wild type. In response to the combined simulation with DEX and TPA, the mutants showed 30-40% of the trancriptional activity of the wild type. Basal transcriptional activity of all the TRE mutants was significantly lower than that of the wild type. While they almost could not bind to c-Jun, their binding affinity to GR was comparable to that of the wild type. Whereas the DEX- and TPA-induced transcriptional activity of 5 TRE mutant was 10% and 15% of that of the wild type, it responded to those agents in a similar pattern as the wild type. The 3 TRE mutant and the mutant of both TRE sites did not respond to DEX and TPA. The GRE-deleted mutant hardly formed the DNA-protein complex as did the wild type, while the GRE -replaced mutant could form the complex in a less amount with nuclear extract of HeLa celL Conclusion: These results suggest that GRE/TRE composite sequence of rat TRH gene specifically binds to GR and c-Jun, providing a site for interaction between the two transcription factors, and that both TRE sites play an important role in basal transcription, and that the 3 TRE site is more critical in the interaction between GRE and TRE for DEX-induced transcriptional activation. (J Kor Endocrinol 14:278-292, 1999)