葡萄糖調控蛋白與鈣網絡蛋白於神經母細胞瘤分化的角色

神經母細胞瘤是一種源自胚胎神經脊中交感神經前驅細胞為最常見的兒童時期腦外實心腫瘤。大多數的孩童在被診斷時疾病已處於晚期或是為轉移的型態。有些轉移的腫瘤能藉由分化或凋亡自行退化或發展成良性的神經節細胞瘤。在先前的研究中我們已鑑定葡萄糖調控蛋白(GRP75)與鈣網絡蛋白(CRT)涉及神經母細胞瘤分化被當作神經母細胞瘤的診斷因子。然而，葡萄糖調控蛋白及鈣網絡蛋白於神經母細胞瘤分化的機制還未明瞭。於現今第一部分的研究中我們證實葡萄糖調控蛋白能和維甲酸細胞核alpha受體(RARα)及類視黃醇alpha受體(RXRα)形成綜合體去調控維甲酸引起的神經分化。葡萄糖調控蛋白藉由增加維甲酸細胞核alpha受體及類視黃醇alpha受體的蛋白質穩定度調控維甲酸細胞核alpha受體及類視黃醇alpha受體的反式激活作用。第二部份的研究我們鑑定鈣網絡蛋白藉由它的鈣調節功能參與在神經生長因子促使的分化中。大量表現鈣網絡蛋白能向上調節MAPK信號傳遞促進神經生長因子引起的分化及藉由向下調控Akt路徑產生凋亡。此外，鈣網絡蛋白能調控MYCN的表現量於轉錄程度。整體而言，我們的研究結果提供了基礎於未來設計新的增進神經母細胞瘤病患存活率的治療策略。

關鍵字

神經母細胞瘤；葡萄糖調控蛋白；鈣網絡蛋白；神經分化；維甲酸；神經生長因子

並列摘要

Neuroblastoma (NB) is the most common extracranial solid tumor of children and is originated from primitive sympathetic neural precursors derived from neural crest. Most children have advanced or metastatic status of disease at diagnosed age. Some of these metastatic tumors can spontaneously regress or mature into a benign ganglioneuroma by undergoing differentiation or apoptosis. In previous research, we have identified that glucose-regulated protein 75 (GRP75) and calreticulin (CRT) were the factors that involved in neuroblastoma differentiation as the prognostic indicator for NB. However, the mechanisms underlying the GRP75 and CRT on neuronal differentiation of NB remain elusive. In the first part of present studies, we have demonstrated that GRP75 could form a complex with retinoic acid receptor alpha (RARα)/rexinoid receptor alpha (RXRα) to modulate retinoic acid (RA)-elicited neuronal differentiation. The transactivation of RARα/RXRα was regulated by GRP75 through increasing the protein stability of RARα/RXRα. In the second part, we identified that CRT participated in nerve growth factor (NGF)-induced differentiation by its Ca2+ buffering function. Overexpression of CRT promoted NGF-mediated differentiation by upregulation mitogen-activated protein kinase (MAPK) signaling and induced apoptosis through downregulation Akt pathway. Furthermore, CRT regulated v-myc myelocytomatosis viral related oncogene (MYCN) expression at the transcriptional level. Collectively, our data provide the basis for designing new therapeutic strategies to improve survival rate of NB patients in the future.

並列關鍵字

Neuroblastoma ； GRP75 ； CRT ； Neuronal differentiation ； Retinoic acid ； NGF

參考文獻

Adamson, P. C., Matthay, K. K., O'Brien, M., Reaman, G. H., Sato, J. K., and Balis, F. M. (2007). A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study. Pediatr Blood Cancer 49, 661-665.

Aitchison, J. D., Blobel, G., and Rout, M. P. (1996). Kap104p: a karyopherin involved in the nuclear transport of messenger RNA binding proteins. Science 274, 624-627.

Aloyz, R. S., Bamji, S. X., Pozniak, C. D., Toma, J. G., Atwal, J., Kaplan, D. R., and Miller, F. D. (1998). p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. The Journal of cell biology 143, 1691-1703.

Anderson, D. J. (1993). Molecular control of cell fate in the neural crest: the sympathoadrenal lineage. Annual review of neuroscience 16, 129-158.

Balmer, J. E., and Blomhoff, R. (2002). Gene expression regulation by retinoic acid. J Lipid Res 43, 1773-1808.

國際替代計量

葡萄糖調控蛋白與鈣網絡蛋白於神經母細胞瘤分化的角色

全文下載

主題瀏覽