Integrin-associated protein簡稱IAP或CD47。IAP是一個分子量50 KD大小的膜蛋白，它會表現在神經系統及免疫系統等組織中。IAP已被證實是一個與記憶相關的基因。在學習與記憶過程中，IAP的表現量會被誘發而增加。功能性研究中，抑制IAP的功能會降低動物嫌惡學習模式的記憶分數。為了瞭解IAP的表現是如何被調控的，我們選殖了一段人類IAP基因啟動子靠5’端的片段，並且在人類神經母細胞株IMR-32、肝癌細胞株HepG2及初代培養的胚胎鼠皮層細胞上，來研究IAP基因啟動子的活性。在不同長度的啟動子活性分析上，發現核心啟動子片段位於轉譯起始點前-232到-12的位置上。利用突變分析法及gel electrophoretic mobility shift assay證實，具有一Alpha-Pal/NRF-1結合序列位於核心啟動子上。Competition assay和supershift assay也同時證明alpha-Pal/NRF-1這個轉錄因子確實可以結合在這一段序列上。在細胞內大量表現alpha-Pal/NRF-1蛋白，可以促進alpha-Pal/NRF-1與核酸結合的能力。大量表現完整的alpha-Pal/NRF-1會促進IAP基因的啟動子活性。反之，大量表現具核酸結合能力但不具轉錄活性的alpha-Pal/NRF-1突變蛋白，則會抑制IAP基因的啟動子活性。這些現象同時在培養下的人類細胞株及初代培養的胚胎鼠皮層細胞都可觀察到。根據以上的實驗，我們發現了轉錄因子alpha-Pal/NRF-1是調控人類IAP基因表現的必要因子。
　　本篇論文的第二部份主要在探討轉錄因子alpha-Pal/NRF-1在神經細胞的功能。我們將帶有alpha-Pal/NRF-1與綠螢光蛋白基因的質體送入細胞內，並且量測這些細胞神經突的相關參數來探討alpha-Pal/NRF-1在神經分化的角色。穩定或短暫大量表現完整的alpha-Pal/NRF-1會顯著誘發神經突生長，同時也會促進神經突的長度，這個現象無論細胞是培養在含百分之十胎牛血清的正常培養基下，或不含血清的培養基下都可觀察到。相對而言，表現突變的alpha-Pal/NRF-1則會抑制神經突的誘發與延展。外送完整alpha-Pal/NRF-1在小鼠神經母細胞株Neuro-2A、神經生長因子誘發的PC12細胞以及初代培養的胚胎鼠皮層細胞，也都同時可觀察到神經突增生的現象。表示這一現象具有普遍性，而不是只發生在人類神經母細胞株上。將細胞培養在可誘發神經突的無血清培養基時，發現alpha-Pal/NRF-1的核酸結合能力及其下游基因IAP的表現量都會增加。送入反向序列的IAP基因，則會抑制alpha-Pal/NRF-1所誘發的神經突生長功能。以上這些發現指出，alpha-Pal/NRF-1在神經細胞的其中一項功能是去調控神經突生長，而這個現象部分而言，是透過alpha-Pal/NRF-1的下游基因IAP來調控。

　Integrin-associated protein (IAP or CD47) is a 50 KD transmembrane protein and expressed in a variety of tissues, including the nervous system and immune system. IAP has been identified as a memory-related gene. It was upregulated during the process of learning and memory. Functional blockage of IAP function also decreased retention score in aversive learning. To understand how cells control the expression of the IAP gene, we cloned the 5' proximal region of the human IAP gene and investigated IAP promoter activity by transient transfection in the human neuroblastoma IMR-32, hepatoma HepG2 cells and primary cortical cells. Deletion analysis identified a core promoter of the human IAP gene located between nucleotide positions -232 and -12 relative to the translation initiation codon. Site-directed mutagenesis and gel electrophoretic mobility shift assay identified an alpha-Pal/NRF-1 binding element within the IAP core promoter. Competition assays and supershift assays using the alpha-Pal/NRF-1 antiserum confirmed the binding of this transcription factor on the alpha-Pal/NRF-1 site. Overexpression of the DNA-binding domain of alpha-Pal/NRF-1 in cells enhanced DNA-alpha-Pal/NRF-1 binding in vitro. Furthermore, overexpression of full-length alpha-Pal/NRF-1 significantly enhanced IAP promoter activity while overexpression of dominant-negative mutant reduced promoter activity both in the cultured human cell lines and primary mouse cortical cells. These results revealed that alpha-Pal/NRF-1 is an essential transcription factor in regulating human IAP gene expression.
　The second part of this thesis is to study the functions of alpha-Pal/NRF-1 in neurons. Transfection of GFP-alpha-Pal/NRF-1 constructs and measurement of neurite parameters were used to evaluate the effects of alpha-Pal/NRF-1 in neuronal differentiation. Stable or transient expression of full-length alpha-Pal/NRF-1 in IMR-32 cells significantly induced neurite outgrowth and increased the length of neurites both in medium containing 10% fetal bovine serum and in serum-free medium. In contrast, the dominant-negative mutant of alpha-Pal/NRF-1 inhibited the induction and extension of neurites. Ectopic expression of full-length alpha-Pal/NRF-1 also increased the induction of neurite outgrowth in Neuro-2A, NGF-treated PC12 cells, and primary mouse cortical neurons. Serum deprivation upregulated the alpha-Pal/NRF-1 binding activity and the expression of the downstream IAP gene. The IAP anti-sense cDNA significantly inhibited the increase of neurite outgrowth by alpha-Pal/NRF-1. These findings indicate that alpha-Pal/NRF-1 plays an important role in regulating neurite outgrowth, partly mediated via its downstream IAP gene.

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