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ABSTRACT: Notch1 genes encode receptors for a signaling pathway that regulates various aspects of cell growth and differentiation; however, the role of Notch1 signaling in p38 mitogen-activated protein kinase (MAPK) signaling pathway is still not well defined. In this study, we found that Notch1 intracellular domain (Notch1-IC) prevents oxidative stress-induced cell death through the suppression of the Apoptosis signal-regulating kinase (ASK) 1 signaling pathway. Notch1-IC inhibited H2O2-induced activation of ASK1 and the activation of downstream kinases in the p38 MAPK signaling cascade. The results of both in vivo binding and kinase studies have revealed that ASK1 is the direct target of Notch1-IC, whereas it produced no effect on either MAP kinase kinase (MKK) 3 or p38 MAPK. Notch1-IC blocked both the homooligomerization of ASK1 and inhibited ASK1 activity. Furthermore, Notch1-IC facilitated the translocation of activated ASK1 toward the nucleus. Notch1 knockdown was determined to be highly susceptible to oxidative stress-induced activation of ASK1-MKK3/MKK6-p38 MAPK signaling cascade and cell death. Taken together, our findings suggest that Notch1-IC may act as a negative regulator in ASK1 signaling cascades.
Proceedings of the National Academy of Sciences 04/2013; · 9.68 Impact Factor
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ABSTRACT: The Notch signaling pathway plays a crucial role in the regulation of cell fate decision, and is also a key regulator of cell differentiation, including bone homeostasis, in a variety of contexts. However, the role of Notch1 signaling in osteoclast differentiation is still controversial. In this study, we show that Receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation is promoted by the Notch1 intracellular domain (Notch1-IC) and Ca(2+)/Calmodulin dependent protein kinase IV (CaMKIV) signaling. Notch1-IC protein level was augmented by CaMKIV through escape from ubiquitin dependent protein degradation. In addition, CaMKIV remarkably increased Notch1-IC stability, and the kinase activity of CaMKIV was essential for facilitating Notch1 signaling. CaMKIV directly interacted with Notch1-IC and phosphorylates Notch1-IC, thereby decreasing proteasomal protein degradation through F-box and WD repeat domain-containing 7 (Fbw7). We also found that Notch1-IC prevented inhibition of osteoclast differentiation by KN-93 but not the phosphorylation deficient form of Notch1-IC. These results suggest that phosphorylated Notch1-IC by CaMKIV increases Notch1-IC stability, which enhances osteoclast differentiation.
Biochimica et Biophysica Acta 10/2012; · 4.66 Impact Factor
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ABSTRACT: Serine-threonine Ca2+/calmodulin-dependent protein kinase II (CaMKII) is the key component in non-canonical Wnt5a signaling and has been shown to regulate its signaling. In this study, we found that CaMKII induced by Wnt5a remarkably reduced the protein stability of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), a co-repressor of Notch signaling, through proteasomal degradation. Wnt5a was found to enhance Notch1 intracellular domain (Notch1-IC) transcription activity, which could be inhibited by treatment with KN93, a CaMKII inhibitor. The kinase activity of CaMKII was essential for the activation of Notch signaling. We also determined that CaMKII could enhance the association between Notch1-IC and RBP-Jk. Furthermore, the physical association between RBP-Jk and SMRT was substantially suppressed by CaMKII. We demonstrated that CaMKII directly bound and phosphorylated SMRT at Ser1407, thereby facilitating SMRT translocation from the nucleus to the cytoplasm and proteasome dependent degradation. These results suggest that CaMKII down-regulated the protein stability of SMRT through proteasomal degradation.
Journal of Biological Chemistry 08/2012; · 4.77 Impact Factor
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ABSTRACT: In writing, linguistic (i.e., spelling) and nonlinguistic (i.e., arranging strokes or letters) functions are processed by the left and right hemispheres, respectively. The configuration of Korean alphabet, 'Hangul' invokes nonlinguistic, visuospatial functions that other writing systems use less extensively. Patients with Alzheimer's disease (AD) have bilateral involvement of temporoparietal-frontal areas that are responsible for processing language and visuospatial functions.
The aim of this study was to examine the nature of Hangul writing dysfunction, which may be associated with bilateral hemispheric impairments in AD.
A sample of 75 patients with AD and 20 healthy controls (HC) performed a Hangul writing task. Neuroimaging positron emission tomography (PET) data of 22 patients were utilized to measure the regional brain glucose metabolism associated with Hangul writing.
The writing performance of the AD group was significantly reduced and different types of errors were observed as the disease got worse. Glucose hypometabolism correlated with Hangul writing impairment was located in the right occipitotemporal lobe and left temporoparietal lobe.
The PET findings demonstrate that impairment in Hangul writing performance in Korean AD patients is closely related to a functional decline in both the right and left hemispheres. The study provides a unique contribution to the knowledge of dysgraphia in a non-alphabetical writing system as well as the underlying neuropathology of dysgraphic features in such languages.
Journal of the neurological sciences 07/2012; 320(1-2):72-8. · 2.32 Impact Factor
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ABSTRACT: Transcriptional regulation performs a central role in Notch1 signaling by recombining binding protein Suppressor of Hairless (RBP-Jk)--a signaling pathway that is widely involved in determination of cell fate. Our earlier work demonstrated the possible regulation of the Notch1-RBP-Jk pathway through protein degradation of RBP-Jk; however, the potential regulator for the degradation of RBP-Jk remains to be determined. Here, we report that the expression of endogenous and exogenous RBP-Jk was increased significantly in cells treated with proteasome- and lysosome-specific inhibitors. The effects of these inhibitors on RBP-Jk occurred in a dose- and time-dependent manner. The level of RBP-Jk protein was higher in presenilin-2 (PS2)-knockout cells than in presenilin-1 (PS1)-knockout cells. Furthermore, the level of RBP-Jk was decreased by expression of PS2 in PS1 and PS2 double-knockout cells. We also found that PS1-knockout cells treated with a specific inhibitor of p38 mitogen-activated protein kinase ∂ (MAPK) had significantly increased levels of RBP-Jk. p38 MAPK phosphorylates RBP-Jk at Thr339 by physical binding, which subsequently induces the degradation and ubiquitylation of the RBP-Jk protein. Collectively, our results indicate that PS2 modulates the degradation of RBP-Jk through phosphorylation by p38 MAPK.
Journal of Cell Science 02/2012; 125(Pt 5):1296-308. · 6.11 Impact Factor
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Jung-Soon Mo, Ji-Hye Yoon,
Ji-Ae Hong,
Mi-Yeon Kim,
Eun-Jung Ann,
Ji-Seon Ahn,
Su-Man Kim,
Hyeong-Jin Baek,
Florian Lang,
Eui-Ju Choi,
Hee-Sae Park
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ABSTRACT: The gamma-secretase complex is involved in the intramembranous proteolysis of a variety of substrates, including the amyloid precursor protein and the Notch receptor. Nicastrin (NCT) is an essential component of the gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we determined that serum- and glucocorticoid-induced protein kinase 1 (SGK1) markedly reduced the protein stability of NCT. The SGK1 kinase activity was decisive for NCT degradation and endogenous SGK1 inhibited gamma-secretase activity. SGK1 downregulates NCT protein levels via proteasomal and lysosomal pathways. Furthermore, SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. Collectively, our findings indicate that SGK1 is a gamma-secretase regulator presumably effective through phosphorylation and degradation of NCT.
PLoS ONE 01/2012; 7(5):e37111. · 4.09 Impact Factor
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ABSTRACT: We investigated confrontation naming performance of patients with Alzheimer's disease (AD) and normal children (NC) to see if the nature of naming performance of AD patients is the reversal of that in normal development. Sixty items of the Boston Naming Test were given to 78 AD patients (and 40 age- and education-matched normal elderly) and 1,080 NC (3- to 14-year-olds). The analyses revealed that, firstly, the naming abilities of the AD patients demonstrated an inverse relationship with those of the NC. Secondly, from the clinical point of view, AD patients tended to lose vocabulary acquired later first while maintaining those acquired in earlier stages of development. Based on the findings, we claimed that this phenomenon was 'a nominal retrogenesis' in which 'retrogenesis' is 'the process by which degenerative mechanisms reverse the order of acquisition in normal development' as defined by Reisberg and colleagues.
European Neurology 09/2011; 66(4):195-9. · 1.81 Impact Factor
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ABSTRACT: Notch signaling involves the proteolytic cleavage of the transmembrane Notch receptor after binding to its transmembrane ligands. Jagged-1 also undergoes proteolytic cleavage by gamma-secretase and releases an intracellular fragment. In this study, we have demonstrated that the Jagged-1 intracellular domain (JICD) inhibits Notch1 signaling via a reduction in the protein stability of the Notch1 intracellular domain (Notch1-IC). The formation of the Notch1-IC-RBP-Jk-Mastermind complex is prevented in the presence of JICD, via a physical interaction. Furthermore, JICD accelerates the protein degradation of Notch1-IC via Fbw7-dependent proteasomal pathway. These results indicate that JICD functions as a negative regulator in Notch1 signaling via the promotion of Notch1-IC degradation.
Experimental Cell Research 07/2011; 317(17):2438-46. · 3.58 Impact Factor
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ABSTRACT: Notch signaling involves the proteolytic cleavage of the transmembrane Notch receptor after binding to its transmembrane ligands. The Delta-like ligand 1 also undergoes proteolytic cleavage upon Notch binding, resulting in the production of a free intracellular domain. In this study, we have demonstrated that the Delta-like 1 intracellular domain (Dll1-IC) specifically binds to Notch1-IC in the nucleus, thereby disrupting the association of the Notch1-IC-RBP-Jk-MAM transcription activator complex. Additionally, the Notch1-mediated blockage of the induction of MyoD is abolished by the co-expression of Dll1-IC. Collectively, our results show that Dll1-IC functions as a negative regulator in Notch signaling via the disruption of the Notch1-IC-RBP-Jk complex.
Molecules and Cells 06/2011; 32(2):161-5. · 2.18 Impact Factor
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Mi-Yeon Kim,
Jung-Soon Mo,
Eun-Jung Ann, Ji-Hye Yoon,
Jane Jung,
Yun-Hee Choi,
Su-Man Kim,
Hwa-Young Kim,
Ji-Seon Ahn,
Hangun Kim,
Kwonseop Kim,
Hyang-Sook Hoe,
Hee-Sae Park
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ABSTRACT: The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC-RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.
Journal of Cell Science 06/2011; 124(Pt 11):1831-43. · 6.11 Impact Factor
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ABSTRACT: Agraphia in Korean patients may be different from agraphia in other patients who use alphabetical writing systems due to the "visuoconstructional script" characteristics of the Korean writing system, Hangul. Patients with early onset Alzheimer's disease (EOAD) have a severe degree of hypometabolism in the parietal area, which is known to be involved in processing visuospatial function. Thus, we explored the diverse error patterns manifested in writing single syllables in Korean patients with EOAD.
A study sample of 35 patients with EOAD and 18 healthy controls (HC) performed a Hangul writing task. We analyzed the erroneous responses of the subjects according to visuoconstructional and linguistic characteristics. In addition, we evaluated the relationship between Hangul writing and the neuropsychological variables as well as the severity of dementia.
When comparing the total number of erroneous responses between EOAD and HC groups, the performances of EOAD patients were significantly worse than those of HC. EOAD patients demonstrated visuoconstructional errors even in the early stages of the disease. Severity of dementia and multiple cognitive domains such as attention, language, immediate memory, and frontal executive functions significantly correlated with the performance of Hangul writing.
Our findings suggest that patients with EOAD exhibit not only linguistic errors but also visuoconstructional manifestations of agraphia, which are associated with cognitive impairments in the multiple domains.
International Psychogeriatrics 05/2011; 23(8):1317-26. · 2.24 Impact Factor
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Eun-Jung Ann,
Hwa-Young Kim,
Yun-Hee Choi,
Mi-Yeon Kim,
Jung-Soon Mo,
Jane Jung, Ji-Hye Yoon,
Su-Man Kim,
Jeong-Sik Moon,
Mi-Sun Seo,
Ji-Ae Hong,
Won-Gu Jang,
Paul Shore,
Toshihisa Komori,
Jeong-Tae Koh,
Hee-Sae Park
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ABSTRACT: Notch1 genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch1 signaling in osteogenesis is not well defined. Notch1 controls osteoblast differentiation by affecting Runx2, but the question arises whether normal osteoblastic differentiation can occur regardless of the presence of Notch1. In this study, we observed the downregulation of Notch1 signaling during osteoblastic differentiation. BMPR-IB/Alk6-induced Runx2 proteins reduced Notch1 activity to a marked degree. Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1-IC-RBP-Jk complex. Using deletion mutants, we also determined that the N-terminal domain of Runx2 was crucial to the binding and inhibition of the N-terminus of the Notch1 intracellular domain. Notably, upregulation of the Runx2 protein level paralleled reduced expression of Hes1, which is a downstream target of Notch1, during osteoblast differentiation. Collectively, our data suggest that Runx2 is an inhibitor of the Notch1 signaling pathway during normal osteoblast differentiation.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2011; 26(2):317-30. · 6.04 Impact Factor
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Jung-Soon Mo,
Eun-Jung Ann, Ji-Hye Yoon,
Jane Jung,
Yun-Hee Choi,
Hwa-Young Kim,
Ji-Seon Ahn,
Su-Man Kim,
Mi-Yeon Kim,
Ji-Ae Hong,
Mi-Sun Seo,
Florian Lang,
Eui-Ju Choi,
Hee-Sae Park
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ABSTRACT: Notch is a transmembrane protein that acts as a transcriptional factor in the Notch signaling pathway for cell survival, cell death and cell differentiation. Notch1 and Fbw7 mutations both lead the activation of the Notch1 pathway and are found in the majority of patients with the leukemia T-ALL. However, little is known about the mechanisms and regulators that are responsible for attenuating the Notch signaling pathway through Fbw7. Here, we report that the serum- and glucocorticoid-inducible protein kinase SGK1 remarkably reduced the protein stability of the active form of Notch1 through Fbw7. The protein level and transcriptional activity of the Notch1 intracellular domain (Notch1-IC) were higher in SGK1-deficient cells than in SGK1 wild-type cells. Notch1-IC was able to form a trimeric complex with Fbw7 and SGK1, thereby SGK1 enhanced the protein degradation of Notch1-IC via a Fbw7-dependent proteasomal pathway. Furthermore, activated SGK1 phosphorylated Fbw7 at serine 227, an effect inducing Notch1-IC protein degradation and ubiquitylation. Moreover, accumulated dexamethasone-induced SGK1 facilitated the degradation of Notch1-IC through phosphorylation of Fbw7. Together our results suggest that SGK1 inhibits the Notch1 signaling pathway via phosphorylation of Fbw7.
Journal of Cell Science 01/2011; 124(Pt 1):100-12. · 6.11 Impact Factor
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ABSTRACT: The present study examined the effects of tangeretin, a polymethoxylated flavonone present in citrus fruits, on ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) expression in JB6 P+ mouse skin epidermal cells. Tangeretin suppressed UVB-induced COX-2 expression and transactivation of nuclear factor-κB and activator protein-1 in JB6 P+ cells. Moreover, tangeretin blocked UVB-induced phosphorylation of Akt and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38, and attenuated the phosphorylation of MAPK kinases 1/2, 3/6, and 4. Tangeretin also limited the endogenous generation of reactive oxygen species (ROS), thereby protecting the cells against oxidative stress. However, tangeretin did not scavenge the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and influence the nicotinamide adenine dinucleotide phosphate oxidase activity. These results suggest that the anti-inflammatory effects of tangeretin stem from its modulation of cell signaling and suppression of intracellular ROS generation. Tangeretin may have a potent chemopreventive effect in skin cancer.
Journal of Agricultural and Food Chemistry 01/2011; 59(1):222-8. · 2.82 Impact Factor
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ABSTRACT: We investigated how changes in the writing of 14 Korean stroke patients reflect the unique features of the Korean writing system.
The Korean writing system, Han-geul, has both linguistic and visuospatial/constructive characteristics. In the visuospatial construction of a syllable, the component consonant(s) and vowel(s) must be arranged from top-to-bottom and/or left-to-right within the form of a square. This syllabic organization, unique to Korean writing, may distinguish dysgraphia in Korean patients from the disorder in other languages, and reveal the effects of stroke on visuospatial/constructive abilities.
We compared 2 groups of patients affected by stroke, 1 group with left hemisphere (LH) lesions and the other with right hemisphere (RH) lesions. We instructed them to write from a dictation of 90 monosyllabic stimuli, each presented with a real word cue. Patients had to repeat a target syllable and a word cue, and then to write the target syllable only.
Patients with LH and RH lesions produced qualitatively different error patterns. While the LH lesion group produced primarily linguistic errors, visuospatial/constructive errors predominated in the group with RH lesions. With regard to language-specific features, these Korean patients with RH lesions produced diverse visuospatial/constructive errors not commonly observed in dysgraphia of the English language.
Language-specific writing errors by Korean stroke patients reflect the unique characteristics of Korean writing, which include the arrangement of strokes and graphemes within a square syllabic form by dimensional and spatial rules. These findings support the notion that the Korean writing system possesses a language-specific nature with both linguistic and visuospatial/constructive processes. Distinctive patterns of dysgraphia in the Korean language also suggest interactivity between linguistic and visuospatial/constructive levels of processing. This study is noteworthy for its systematic description of Korean dysgraphia in the largest group of patients studied to date.
Cognitive and behavioral neurology: official journal of the Society for Behavioral and Cognitive Neurology 12/2010; 23(4):247-55. · 1.09 Impact Factor
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ABSTRACT: Patients with Alzheimer disease (AD) usually experience naming difficulty due to storage and access problems in phonological-lexical representation. Investigating naming response patterns followed by cueing may help us to understand the underlying mechanism of naming deficits in AD. A total of 221 patients with mild cognitive impairment and AD [Clinical Dementia Rating (CDR) 0.5, 1, 2] were included as subjects. Sixty items of the Korean version of the Boston Naming Test were given, and upon failure, semantic/syllabic cues were verbally presented. From the results, even in the CDR 2 group, which is considered to be a moderate stage of AD, syllabic cues significantly facilitated correct responses. Our findings are in contrast with previous studies conducted with English-speaking patients, which reported that phonological-lexical representation may have been disrupted in the moderate stage of AD, and that none of the cues facilitated correct word retrieval. The difference may be ascribed to the fact that direct access to the phonological-lexical representation via syllabic cues was possible in the confrontation naming task performed by the Korean patients. It can be concluded that phonological-lexical representation in moderate stage Korean AD might be partially preserved because syllabic cues in AD patients were effective in facilitating target words.
Alzheimer disease and associated disorders 09/2010; · 2.88 Impact Factor
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ABSTRACT: Odontoblasts are involved in tooth repair and regeneration as well as dentin formation. The aim of this study was to examine whether delivery of heat shock protein 27 (Hsp27) into cells using a TAT fusion protein system (TAT-Hsp27) enhances adhesion and migration of murine dental papilla-derived MDPC-23 cells. Hsp27 was delivered into cells by the TAT-fusion protein system. To examine whether TAT-Hsp27 affects the viability of MDPC-23 cells, MTT assay was performed. The effect of TAT-Hsp27 on adhesion and migration of MDPC-23 cells was determined using type I collagen-coated plates and a commercial kit, respectively. In addition, a precise molecular mechanism was examined by Western blot analysis and focal adhesion activity. TAT-fusion protein system delivered Hsp27 into cells successfully. Transduction of TAT-Hsp27 induced adhesion and migration of MDPC-23 cells in a dose-dependent manner. Moreover, transduction of TAT-Hsp27 increased the protein expression of beta1 integrin and focal adhesion formation, and induced phosphorylation of FAK and ERK. TAT-Hsp27-induced migration of MDPC-23 cells was restored by treatment of anti-beta1 integrin antibody. These findings suggest that TAT-Hsp27 promotes adhesion and migration of MDPC-23 cells via beta1 integrin-mediated signaling and is a promising candidate for therapeutic application of dental pulp regeneration.
International Journal of Molecular Medicine 09/2010; 26(3):373-8. · 1.98 Impact Factor
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ABSTRACT: DJ-1 has been reported as a gene linked to early onset familial Parkinson's disease, and is functionally involved in transcriptional regulation and oxidative stress-induced cell death. To understand the role of DJ-1 in cellular stress, this study investigated DJ-1's effect on stress-activated protein kinase signaling and H(2)O(2)-induced activation of apoptosis signal-regulating kinase 1 (ASK1). According to the results, the overexpression of DJ-1 inhibited H(2)O(2)-induced activation of ASK1 as well as the activation of downstream kinases in the p38 mitogen-activated protein kinase (MAPK) signaling cascade. The results of both in vivo binding and kinase studies have revealed that ASK1 is the direct target of DJ-1, whereas it has shown no effect on either MKK3 or p38. DJ-1 blocked both the homo-oligomerization of ASK1 and inhibited ASK1 activity. Taken together, our data strongly suggest that DJ-1, by directly inhibiting ASK1, may act as a negative regulator in ASK1 signaling cascades.
Journal of Cellular Biochemistry 03/2010; 110(1):229-37. · 2.87 Impact Factor
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ABSTRACT: (-)-Epigallocatechin-3-gallate (EGCG) has inhibitory effect on a variety of cancers by inducing apoptosis and cell cycle arrest or inhibiting angiogenesis and metastasis. EGCG has been found to induce apoptosis in salivary gland carcinoma cells, however, it is not known whether EGCG affects invasion and migration. Thus, this study was performed to clarify whether EGCG affects invasion and migration of salivary gland tumors. Matrigel invasion assay, wound scratch assay and migration assay using commercial kit were performed. beta1 integrin expression and activation of its downstream molecules such as focal adhesion kinase (FAK), AKT and extracellular signal-regulated kinase (ERK) were examined by Western blot. Enzymatic activity of matrix metalloprotease (MMP)-2 and MMP-9 was examined by gelatin zymography. EGCG inhibited effectively invasion and migration of SGT cells in a dose-dependent manner. EGCG also inhibited the activation of beta1 integrin-downstream molecules such as FAK, AKT and ERK as well as the expression of beta1 integrin itself. Moreover, MMP-2 and MMP-9 expression and their enzymatic activity were reduced by EGCG in a dose-dependent manner. These results indicate that EGCG may effectively suppress salivary gland tumors by inhibiting metastasis through beta1 integrin-mediated signaling.
Oncology Reports 02/2010; 23(2):585-90. · 1.84 Impact Factor
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ABSTRACT: 5'-Nitro-indirubinoxime (5'-NIO) is a new derivative of indirubin that exhibits anti-cancer activity in a variety of human cancer cells. However, its mechanism has not been fully clarified.
Human salivary gland adenocarcinoma (SGT) cells were used in this study. Western blot and RT-PCR analyses were performed to determine cellular Notch levels. The cell cycle stage and level of apoptosis were analyzed using flow cytometry analysis.
5'-NIO significantly inhibited the mRNA levels of Notch-1 and Notch-3 and their ligands (Delta1, 2, 3, and Jagged-2) in SGT cells. Immunocytochemistry analysis showed that 5'-NIO specifically decreased the level of Notch-1 in the nucleus. In addition, 5'-NIO induced G1 cell cycle arrest by reducing levels of CDK4 and CDK6 in SGT cells. Using flow cytometry and immunoblotting analysis, we found that 5'-NIO induces apoptosis following the secretion of cytochrome c and the activation of caspase-3 and caspase-7. Intracellular Notch-1 overexpression led to a decrease in G1 phase arrest and an inhibition of 5'-NIO-induced apoptosis.
These observations suggest that 5'-NIO induces cell cycle arrest and apoptosis by down-regulating Notch-1 signaling.
This study identifies a new mechanism of 5'-NIO-mediated anti-tumor properties. Thus, 5'-NIO could be used as a candidate for salivary gland adenocarcinoma therapeutics.
Biochimica et Biophysica Acta 11/2009; 1800(3):352-8. · 4.66 Impact Factor
