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한국학술지인용색인(NRF)
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TMP21은 AD의 원인으로 작용하는 Aβ-42 펩타이드 생성에 중요한 γ-secretase 활성을 억제하는 p24 family에 속하는 type I 막 단백질이다. 본 연구에서는 TMP21이 세포의 성장과 분화에 중요한 NGF 수용체 신호전달과정에 미치는 영향을 분석하고자 인간의 TMP21 cDNA를 합성하고, CMV promoter 조절 하에 hTMP21를 클로닝하여, CMV/hTMP21 벡터를 제조하였다. 그리고 이들 벡터를 B35 neuroblastoma에서 과발현시킨 후 γ-secretase 구성단백질과 NGF 수용체 연관 단백질의 변화를 관찰하였다. 그 결과, 4종류의 γ-secretase 구성단백질의 발현은 vehicle transfectants보다 CMV/hTMP21 transfectants에서 유의적으로 감소하였다. 또한 NGF low affinity 수용체인 p75^NTR과 downstream 단백질인 RhoA의 양은 NGF를 처리하지 않은 TMP21 transfectants에서 유의적으로 증가하였으나 NGF 처리에 의해 감소되었다. High affinity NGF 수용체인 TrkA의 인산화도 NGF 처리가 없는 경우 유의적으로 감소하였으나 NGF 처리에 의해 증가되었다. 또한 downstream 신호전달 과정 중에서 ERK의 인산화는 TrkA와 유사한 발현변화를 나타내었으나 Akt 인산화는 NGF의 처리에 의해 더욱 증가하였다. 이러한 결과는 TMP21이 neuroblastoma에서 NGF 수용체 신호전달과정를 조절하는 중요한 단백질로서 작용함을 제시하며, AD의 작용기전 연구에 중요한 기초자료를 제공할 것으로 사료된다.
Transmembrane protein 21 (TMP21) is a member of the p24 cargo protein family and has been shown to modulate γ-secretase-mediated Aβ production which was specifically observed in the brains of subjects with Alzheimer’s disease (AD). In order to investigate whether TMP21 could affect nerve growth factor (NGF) receptor signaling pathway, the alteration of NGF receptors and their downstream proteins were detected in TMP21 over-expressed cells. CMV/hTMP21 vector used in this study was successfully expressed into TMP21 proteins in B35 cells after lipofectamin transfection. Expressed TMP21 proteins induced the down-regulation of γ-secretase complex components including Presenlin-1 (PS-1), PS-2, Nicastrin (NST), Pen-2 and APH-1. Also, the expression level of NGF receptor p75^NTR and RhoA were significantly higher in CMV/hTMP21 transfectants than vehicle transfectants, while their levels returned to vehicle levels after NGF treatment. However, the phosphorylation of NGF receptor TrkA was dramtically decreased in NGF No-treated CMV/hTMP21 transfectants compared with vehicle transfectants, and increased in NGF treated CMV/hTMP21 transfectants. In TrkA downstream signaling pathway, the phosphorylation level of ERK was also decreased in CMV/hTMP21 transfectants, while the phosphorylation of Akt was increased in the same transfectants. Furthermore, NGF treatment induced the increase of phosphorylation level of Akt and ERK in CMV/hTMP21 transfectants. Therefore, these results suggested that over-expression of TMP21 may simultaneously induce the up-regulation of p75^NTR/RhoA expression and the down-regulation of TrkA/ERK phosphorylation through the inhibition of γ-secretase activity.
Transmembrane protein 21 (TMP21) is a member of the p24 cargo protein family and has been shown to modulate γ-secretase-mediated Aβ production which was specifically observed in the brains of subjects with Alzheimer’s disease (AD). In order to investigate whether TMP21 could affect nerve growth factor (NGF) receptor signaling pathway, the alteration of NGF receptors and their downstream proteins were detected in TMP21 over-expressed cells. CMV/hTMP21 vector used in this study was successfully expressed into TMP21 proteins in B35 cells after lipofectamin transfection. Expressed TMP21 proteins induced the down-regulation of γ-secretase complex components including Presenlin-1 (PS-1), PS-2, Nicastrin (NST), Pen-2 and APH-1. Also, the expression level of NGF receptor p75^NTR and RhoA were significantly higher in CMV/hTMP21 transfectants than vehicle transfectants, while their levels returned to vehicle levels after NGF treatment. However, the phosphorylation of NGF receptor TrkA was dramtically decreased in NGF No-treated CMV/hTMP21 transfectants compared with vehicle transfectants, and increased in NGF treated CMV/hTMP21 transfectants. In TrkA downstream signaling pathway, the phosphorylation level of ERK was also decreased in CMV/hTMP21 transfectants, while the phosphorylation of Akt was increased in the same transfectants. Furthermore, NGF treatment induced the increase of phosphorylation level of Akt and ERK in CMV/hTMP21 transfectants. Therefore, these results suggested that over-expression of TMP21 may simultaneously induce the up-regulation of p75^NTR/RhoA expression and the down-regulation of TrkA/ERK phosphorylation through the inhibition of γ-secretase activity.
권호기사
참고문헌 (30건) : 자료제공( 네이버학술정보 )
| 번호 | 참고문헌 | 국회도서관 소장유무 |
|---|---|---|
| 1 | Traffic COPs of the Early Secretory Pathway  |
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| 2 | Tmp21 and p24A, two type I proteins enriched in pancreatic microsomal membranes, are members of a protein family involved in vesicular trafficking. |
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| 3 | Intracellular localization and in vivo trafficking of p24A and p23. |
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| 4 | TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. |
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| 5 | Choi, S. I., J. H. Park, Y. K. Her, Y. K. Lee, J. E. Kim, S. H. Nam, J. S. Goo, M. J. Jang, H. S. Lee, H. J. Son, C. Y. Lee, and D. Y. Hwang. 2010. Effects of water extract of Liriope platyphylla on the m RNA expression and protein secretion of nerve growth factors. Korean J. Medicinal Crop Sci. 18, 291-297. | 미소장 |
| 6 | Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active γ-Secretase Complex |
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| 7 | Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. |
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| 8 | Gastroenterology news |
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| 9 | TMP21 regulates Aβ production but does not affect caspase-3, p53, and neprilysin |
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| 10 | A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception |
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| 11 | The nerve growth factor and its receptors in airway inflammatory diseases. |
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| 12 | Gu, L., W. Yao, Z. Yan, L. Xie, D. Sun, D. Li, Z. Zeng, and Z. Wen. 2003. Effects of TFAR19 gene on the growth and biorheological properties of mouse erythroleukemia cell line MEL. Sci. China C. Life. Sci. 46, 293-301. | 미소장 |
| 13 | Familial Alzheimer's disease presenilin 1 mutation M146V increases gamma secretase cutting of p75NTR in vitro |
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| 14 | Nerve Growth Factor, Neural Stem Cells and Alzheimer's Disease |
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| 15 | Alterations in behavior, amyloid beta-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer's disease. |
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| 16 | Changes in presenilin 2-binding Wnt proteins, behavior, amyloid-β 42, γ-secretase activity, and testosterone sensitivity in transgenic mice coexpressing tetracycline-controlled transactivator and human mutant presenilin 2 |
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| 17 | The γ-secretase complex: machinery for intramembrane proteolysis |
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| 18 | Role of p75 Neurotrophin Receptor in the Neurotoxicity by β-amyloid Peptides and Synergistic Effect of Inflammatory Cytokines |
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| 19 | Signal transduction through tyrosine-phosphorylated C-terminal fragments of amyloid precursor protein via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. |
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| 20 | PEN-2 overexpression induces gamma-secretase protein and its activity with amyloid beta-42 production. |
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| 21 | Immature nicastrin stabilizes APH‐1 independent of PEN‐2 and presenilin: identification of nicastrin mutants that selectively interact with APH‐1 |
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| 22 | Identification of Distinct γ-Secretase Complexes with Different APH-1 Variants |
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| 23 | Susen, K. and A. Blöchl. 2005. Low concentrations of aggregated β-amyloid induce neurite formation via the neurotrophin receptor p75. J. Mol. Med. 83, 720-735. | 미소장 |
| 24 | Tyrosine Phosphorylation of the -Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc |
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| 25 | Characterization of an NGF-P-TrkA retrograde-signaling complex and age-dependent regulation of TrkA phosphorylation in sympathetic neurons. |
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| 26 | BACE1: the beta-secretase enzyme in Alzheimer's disease. |
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| 27 | The Role of Presenilin and its Interacting Proteins in the Biogenesis of Alzheimer’s Beta Amyloid |
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| 28 | Dual roles of the transmembrane protein p23/TMP21 in the modulation of amyloid precursor protein metabolism. |
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| 29 | p75NTR Regulates A Deposition by Increasing A Production But Inhibiting A Aggregation with Its Extracellular Domain |
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| 30 | Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. |
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