1.Merlin Represses Ras-Induced Cyclin D1 Transcription through the Cyclic AMP-Responsive Element.
Noh Jin KWAK ; Hongtae KIM ; Byung Hyune CHOI ; Young Hoon KIM ; Hyoung Kyun RHA ; Kweon Haeng LEE
The Korean Journal of Physiology and Pharmacology 2003;7(5):289-293
Mutations in the NF2 tumor suppressor gene cause neurofibromatosis type 2, an autosomal dominant inherited syndrome predisposed to the multiple tumors of the nervous system. Merlin, the NF2 gene product was reported to block Ras-mediated cell transformation and represses Ras-induced expression of cyclin D1. However, the potential mechanism underlying the anti-Ras function of merlin on the cyclin D1 is still unclear. In this study, we investigated whether merlin decreases Ha-ras-induced accumulation of cyclin D1 at the transcriptional level, and demonstrated that merlin suppressed Ras-induced cyclin D1 promoter activity mediated by the cyclic AMP-responsive element (CRE) in SK-N-BE (2) C neuroblastoma cells. Furthermore, we found that merlin attenuated active Ras and forskolin-induced CRE-driven promoter activity. These results suggest that the transcriptional repression of the cyclin D1 expression by merlin may contribute to the inhibition of Ras-induced cell proliferation
Cell Proliferation
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Cyclin D1*
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Cyclins*
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Genes, Tumor Suppressor
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Nervous System Neoplasms
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Neuroblastoma
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Neurofibromatosis 2
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Neurofibromin 2*
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Repression, Psychology
2.Expression of Ezrin in Vagina Cells of Postmenopausal Rats after Dietary Administration of Omega-3 Fatty Acid Formula.
Hae Hyeog LEE ; Tae Hee KIM ; Junsik PARK ; Arum LEE ; Yongsoon PARK ; Dong Won BYUN ; Min Jung KIM ; Heesook LIM
Journal of Menopausal Medicine 2014;20(3):97-103
OBJECTIVES: To see the effect of dietary administration of omega 3-fatty acid formula on the vaginal cells of postmenopausal rats. METHODS: Three-week-old female Wistar/ST rats were raised after one week of adjustment period. The rats were then divided into three groups, for three different kinds of diet; general diet, 1% omega-3 fatty acid diet, and 2% omega-3 fatty acid diet. After eight weeks of having assigned diet, after the oophorectomy, with the same diet previously they had Immunohistochemistry, Immunofluorescence, and Western Blot about ezrin, merlin were done. RESULTS: In immunohistochemistry, estrogen injection group revealed thicker and well differentiated features. In Immunofluorescence, Omega-3 fatty acid composition in diet did not effect expression of ezrin and merlin in rat vagina in estrogen injection group, their vaginal epithelium showed full layers (from basal to apical layer). In Western Blot analysis, Omega-3 fatty acid composition in diet did not affect expression of ezrin and merlin in rat vagina estrogen presented significant impact on expression of ezrin and merlin. CONCLUSION: Although omega-3 fatty acid composition changed in diet, vaginal epithelial morphology unchanged. Estrogen did effect on vagina cell, but omega-3 fatty acid did not effect on ezrin and merlin in vagina.
Animals
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Atrophic Vaginitis
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Blotting, Western
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Diet
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Epithelium
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Estrogens
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Female
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Fluorescent Antibody Technique
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Humans
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Immunohistochemistry
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Neurofibromin 2
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Ovariectomy
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Rats*
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Vagina*
3.The Similarities and Differences between Intracranial and Spinal Ependymomas : A Review from a Genetic Research Perspective.
Chang Hyun LEE ; Chun Kee CHUNG ; Jung Hun OHN ; Chi Heon KIM
Journal of Korean Neurosurgical Society 2016;59(2):83-90
Ependymomas occur in both the brain and spine. The prognosis of these tumors sometimes differs for different locations. The genetic landscape of ependymoma is very heterogeneous despite the similarity of histopathologic findings. In this review, we describe the genetic differences between spinal ependymomas and their intracranial counterparts to better understand their prognosis. From the literature review, many studies have reported that spinal cord ependymoma might be associated with NF2 mutation, NEFL overexpression, Merlin loss, and 9q gain. In myxopapillary ependymoma, NEFL and HOXB13 overexpression were reported to be associated. Prior studies have identified HIC-1 methylation, 4.1B deletion, and 4.1R loss as common features in intracranial ependymoma. Supratentorial ependymoma is usually characterized by NOTCH-1 mutation and p75 expression. TNC mutation, no hypermethylation of RASSF1A, and GFAP/NeuN expression may be diagnostic clues of posterior fossa ependymoma. Although MEN1, TP53, and PTEN mutations are rarely reported in ependymoma, they may be related to a poor prognosis, such as recurrence or metastasis. Spinal ependymoma has been found to be quite different from intracranial ependymoma in genetic studies, and the favorable prognosis in spinal ependymoma may be the result of the genetic differences. A more detailed understanding of these various genetic aberrations may enable the identification of more specific prognostic markers as well as the development of customized targeted therapies.
Brain
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Ependymoma*
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Genetic Research*
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Genetics
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Methylation
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Multiple Endocrine Neoplasia Type 1
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Neoplasm Metastasis
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Neurofibromin 2
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Prognosis
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Recurrence
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Spinal Cord
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Spine
4.Expression of S518 phosphorylated Merlin and its interaction with CD44 in vestibular schwannoma.
Li-hui CAI ; Hao WU ; Jing-rong LÜ ; Zhao-yan WANG
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2008;43(12):910-914
OBJECTIVETo investigate the impact of S518 phosphorylation in Merlin on the interaction with CD44 in vestibular schwannoma and the tumor growth.
METHODSThirty-five samples of vestibular schwannoma were identified by pathology. Immunohistopathology and western blot were employed to analyze the expression and localization of S518 phosphorylated Merlin in the tumor tissues. Nerve tissues that were collected during other surgical operation were used as control. The expression level of S518 phosphorylated Merlin was compared with clinical stages, tumor size, clinical course and cystic degeneration. Immunoprecipitation was used to evaluate the impact of S518 phosphorylation in Merlin on the interaction with CD44.
RESULTSIn vestibular schwannoma, Merlin was phosphorylated at S518 and demonstrated perinuclear localization. The S518 phosphorylation level was much lower in the normal control nerve tissues than that in vestibular schwannoma tissues. There was no correlation between the phosphorylation level on Merlin and clinical stages, tumor size, clinical course and cystic degeneration. The S518 phosphorylated Merlin bound CD44 was higher than wild-type Merlin bound CD44 in vestibular schwannoma tissues.
CONCLUSIONSThe affinity of Merlin to CD44 was increased after phosphorylation at S518. Different cellular biological results might be triggered through binding to wild type Merlin and S518 phosphorylated Merlin.
Adult ; Aged ; Female ; Genes, Neurofibromatosis 2 ; Humans ; Hyaluronan Receptors ; genetics ; metabolism ; Male ; Middle Aged ; Neoplasm Staging ; Neurofibromin 2 ; genetics ; metabolism ; Neuroma, Acoustic ; genetics ; metabolism ; pathology ; Phosphorylation
5.Expression of Merlin protein in non-small cell lung carcinoma and the clinical significance.
Jianpeng HU ; Li WANG ; Fenglei YU
Journal of Central South University(Medical Sciences) 2011;36(6):565-569
OBJECTIVE:
To determine the expression and clinical significance of Merlin protein in non-small cell lung cancer (NSCLC).
METHODS:
The expression of Merlin protein in 45 cases of NSCLC and adjacent tissue of NSCLC and normal lung tissue was checked by immunohistochemistry. The relation between the expression of Merlin protein and the multiple factors of pathological type, gender, P-TNM stage, differentiation and lymph node metastasis was analyzed.
RESULTS:
The expression rates of Merlin protein in NSCLC and normal lung tissue sections were 73.33% and 15.56%, respectively (P<0.05). The expression of Merlin protein was not associated with the pathological type, gender, P-TNM stage, differentiation and lymph node metastasis (P>0.05).
CONCLUSION
Merlin protein might contribute to the initiation of metastasis of NSCLC.
Adult
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Aged
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Carcinoma, Non-Small-Cell Lung
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metabolism
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pathology
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Female
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Genes, Neurofibromatosis 2
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physiology
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Humans
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Lung Neoplasms
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metabolism
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pathology
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Male
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Middle Aged
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Neoplasm Metastasis
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Neurofibromin 2
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metabolism
6.Expression and localization of merlin in vestibular schwannoma.
Jing-Rong LÜ ; Jing ZOU ; Hao WU
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2006;41(7):501-505
OBJECTIVETo clarify the expression and subcellular localization of merlin in vestibular schwannoma.
METHODSFifty four paraffin embedded vestibular schwannoma samples confirmed by pathology after resection were included in the study. The expression of merlin in vestibular schwannoma was analyzed by immunohistochemistry. Nerve tissues that were resected during surgical treatment for trigeminal neuralgia and Meniere's disease were used as control. Western blotting was used to analyze the electrophoresis migration of merlin in the acoustic neuroma. Image analysis was used to calculate the positive expression percentage of merlin in each individual. The expression percentage of merlin in the tumor tissue was compared with age and gender of the patients, clinical course of the tumor, tumor growth index, tumor diameter and clinical stage.
RESULTSMerlin was expressed in 0 to 87.5% of the cells in vestibular schwannoma tissue with a mean of (46.66 +/- 5.75)%. There was a negative correlation between merlin expression percentage and tumor growth index. There were no correlations between merlin expression percentage and the age, gender, tumor diameter and clinical stage. There exists a difference for the location of merlin, mainly in the nucleus and perinucleus. There was also a cytoplasmic location. Merlin in the tumor tissue was shown by western blot to be in 65000 and 125000 positions.
CONCLUSIONSMerlin was expressed in vestibular schwannoma tissue, with a different intra-cellular location. Merlin might also exist as a complex with other proteins in the tumor tissue.
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Neurofibromin 2 ; metabolism ; Neuroma, Acoustic ; metabolism ; pathology ; Young Adult
7.Merlin; NF2 Tumor Suppressor and Regulator of Receptor Distribution/Signaling.
Korean Journal of Otolaryngology - Head and Neck Surgery 2011;54(6):379-385
Acoustic tumor is the most common tumor originating from cerebellopontine angle. Acoustic tumor is benign and main origin of this tumor is vestibular nerve. This tumor arises in Schwann cell (SC) and is encapsulated. Recently, the tumor is called vestibular schwannoma (VS). VS is classified to two type by epidemiology, sporadic form and neurofibromatosis type 2 (NF2). NF2 is autosomal dominant inherent disorder. This tumor is characterized bilateral VS, brain tumors such as meningioma and ependymoma, and spinal or cranial nerve schwannoma. Genetic studies suggested that NF2 is caused by abnormality or mutation of NF2 gene in chromosome 22q12. Both of them are known to develop the tumor by mutation of NF2 gene. Merlin is the cytoskeletal protein product of the NF2 tumor suppressor gene that mediates cell to cell contact information to regulate SC proliferation and survival. And merlin is highly homologous to ERM proteins. Merlin function is regulated by its conformation, adopting an inactive, growth permissive state following serine 518 (S518) phosphorylation. In NF2 patients, the precise mechanisms of developing the VS are unclear. But, the abnormalities of merlin are confirmed by many studies. And now, a lot of research about merlin function is progressing. In this study, the author would introduce about merlin (structure, function, molecular pathway, tumorigenesis and regulation) which leads to VS and molecular studies about merlin, and suggest the future direction of research.
Brain Neoplasms
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Cell Transformation, Neoplastic
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Cerebellopontine Angle
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Cranial Nerves
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Ependymoma
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Genes, Neurofibromatosis 2
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Genes, Tumor Suppressor
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Humans
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Meningioma
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Neurilemmoma
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Neurofibromatosis 2
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Neurofibromin 2
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Neuroma, Acoustic
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Phosphorylation
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Proteins
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Serine
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Vestibular Nerve
8.Mutation analysis of NF2 gene and clinical investigation in a Chinese family with neurofibromatosis type II.
Ying-xia CUI ; Xin-yi XIA ; Ting-ting HUANG ; Li WEI ; Xiao-bo FAN ; Bing YAO ; Yi-feng GE ; Xiao-jun LI ; Yu-feng HUANG
Chinese Journal of Medical Genetics 2010;27(6):688-691
OBJECTIVETo report a heterozygous RNA-splicing mutation (IVS3+ 3A to C) of NF2 gene in a Chinese family with autosomal dominant neurofibromatosis type II and investigate the relationship between the genotype and phenotype.
METHODSThe proband with bilateral vestibular schwannomas underwent gamma knife radiosurgery two years earlier. DNA of blood samples from all affected individuals, suspected individuals and unaffected relatives of the family was extracted and amplified to detect the polymorphisms at loci D22S1150 and D22S268 that are linked with the NF2 gene. Two-point LOD score was calculated. The promoter region, 17 exons and exon/intron boundaries of NF2 gene were amplified and sequenced for the proband. The exon 3/intron 3 boundaries of NF2 gene was amplified and sequenced for the other 3 patients, 1 suspected individual, 9 unaffected members of the family and 150 unrelated controls.
RESULTSThe result of two-point linkage analysis suggested that NF2 gene was a candidate gene (Zmax= 2.109, θ = 0.00, locus D22S1150). DNA sequencing revealed a heterozygous splicing mutation in intron 3 (IVS3+ 3A to C) for the proband. Identical mutation was also observed in the other 3 patients and 1 suspected individual. No mutation was found in the 9 normal family members and 150 unrelated controls, which was consistent with the clinical diagnosis.
CONCLUSIONThis is the first report of familial neurofibromatosis type II with a splicing mutation of IVS3+ 3A to C of the NF2 gene. The mutation might be responsible for the neurofibromatosis type II in the family.
Adult ; Animals ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; DNA Mutational Analysis ; methods ; Dogs ; Female ; Genetic Linkage ; Humans ; Male ; Mice ; Middle Aged ; Mutation ; genetics ; Neurofibromatosis 2 ; genetics ; pathology ; physiopathology ; Neurofibromin 2 ; genetics ; Pedigree ; RNA Splicing ; genetics ; Sequence Alignment