4E-BP3 為一個分子量14.6 kDa 之蛋白，屬於4E-BPs 家族的一員。
過去研究發現去磷酸化的4E-BPs 會與eIF4G 競爭eIF4E的結合位置，因
此可以抑制cap-dependent 轉譯的速率。在4E-BPs 家族成員之中，4E-BP1
是抑制cap-dependent 轉譯機制的主要蛋白，也因此被研究的較為透徹。
本實驗室先前利用Yeast-Two Hybrid 之方法，由人類乳腺細胞基因庫中，
篩選出另一個replication protein A次單元體RPA2，會與4E-BP3 有交互
作用，這個結果暗示著4E-BP3 的某些功能可能與RPA2 有所關聯。之前
研究發現，4E-BP3 會在人類不同器官中的細胞中表現，不過對於4E-BP3
確實的功能和調控方式卻都還不了解，也尚未比較過4E-BPs 成員之間的
蛋白質表現。因此利用RT-PCR 的方式探討細胞內4E-BPs 的表現，量化
RT-PCR 訊號並求取比值，結果顯示4E-BP1 和4E-BP3 的比值分別在
HEK293T和MCF7 內為3.2 和2.5。顯示4E-BPs 的表現量並非相等而可
能造成對於轉譯作用有重要性的差異。為了觀察4E-BPs 對於細胞轉譯速
率的影響，以luciferase 的活性做為轉譯速度的指標，藉由luciferase 產生
的冷光相對差異即可偵測細胞內轉譯速度的變化。轉譯的起始速率會決
定於eIF4E 蛋白量，以西方墨點法確認了4E-BP3 表現對於eIF4E 蛋白量
不會有明顯的改變，因此轉譯的速度不因為eIF4E 濃度改變而受影響。
細胞內大量表現4E-BP3 後， luciferase 活性有明顯的下降，下降的程度

與4E-BP1 相比稍強，顯示細胞內4E-BPs 對於轉譯速度的功能是類似的。
在先前實驗室已經證明了4E-BP3與eIF4E在細胞核及細胞質當中都有交
互作用存在。而eIF4E 在細胞核內可以幫助特定mRNA向細胞質進行運
送，此類的mRNA 大多與細胞生長週期調控有關，比如cyclin D1 的
mRNA。因此我們驗證了在HEK293T、MCF7 細胞中大量表現4E-BP3
是否因此改變細胞核mRNA向細胞質移動的機制，以西方墨點法分析細
胞中的蛋白質，發現cyclin D1 濃度降低，而mRNA的分析顯示cyclin D1
mRNA濃度沒有改變。同樣的現象也出現在4E-BP3 穩定表現的細胞株。
此外當穩定表現細胞株內的4E-BP3 表現降低時，cyclin D1 蛋白濃度有些
微的上昇；再加上當表現eIF4E 以及只可執行RNA 運送功能的eIF4E突
變蛋白時，穩定表現細胞株內的cyclin D1 蛋白濃度也隨之上升，相同的
現象在表現只可執行轉譯功能的eIF4E 突變蛋白時沒有出現。這些結果
顯示4E-BP3可能藉由抑制mRNA運送的機制改變了cyclin D1或其他生
長相關蛋白的表現。因此4E-BP3 穩定表現的細胞株的增生速度，與控制
組相比有減緩的現象。此外我們也觀察到RPA2 的表現可以加強4E-BP3
在細胞核內的功能，而對於細胞質內4E-BP3 的功能沒有明顯改變，因此
猜測RPA2 也許可以幫助4E-BP3 在細胞核質之間的運送，並且因此影像
到cyclin D1 mRNA的運送過程。

4E-BP3, which is a protein with 14.6 kilo Dalton, belongs to the 4E-BPs
(eukaryotic initiation factor 4E-binding proteins) family. 4E-BPs is able to
compete with eIF4G for binding eIF4E and repress cap-dependent translation.
4E-BP3 was the last 4E-BPs to be identified and its properties have been not
investigated in detail. In our previous study, we found that the endogenous
4E-BP3 was detected in various cells, including U2OS, HeLa, MCF7,
HEK293T, JK, and LNCAP. In addition, we also found that 4E-BP3 interacts
with RPA2 (the second subunit). However the physiological roles of the
interaction remain unknown. In this study, the mRNA of 4E-BP1 and 4E-BP3
in HEK293T and MCF7 cell were determined by RT-PCR and the results
showed the ratio of relative mRNA level of 4E-BP1 to 4E-BP3 is about 3.2:1
in HEK293T cells and is about 2.5:1 in MCF7 cells. To investigate whether
4E-BP1 or 4E-BP3 has an inhibiting affects on protein translation,
co-translation of 4E-BP1 or 4E-BP3 with luciferase report plasmid in to
HEK293T cell were performed and luciferase activities were determined. The
result indicated that ectopic expression of 4E-BP1 resulted in decrease rates
of protein translation when compare with the empty-vector- transfected cells.
Similarly, ectopic expression of 4E-BP3 also result in the decrease rate of
translation when compare with the empty-vector-transfected cells. Previous
study reported that 4E-BP3 is present and associated with eIF4E in both
nucleus and cytoplasm in several cells, and recent studies indicated that the
nuclear eIF4E could promote the nucleo-cytoplasmic export of a subset of
growth-promoting mRNA including cyclinD1. Thus we also examined

whether overexpression of the 4E-BP3 could inhibit the nucleo- cytoplasmic
export of the mRNA of the cyclin D1. The results of our pre- liminary
experiments revealed that ectopic expression of 4E-BP3 in U2OS and
HEK293T cells resulted in decreased cyclin D1 protein level, whereas the
mRNA level of the cyclin D1 remain constant. The decrease in cyclin D1
protein level in our established stably 4E-BP3 overexpressing cells were also
observed when compared with the mock cells. In addition, when 4E-BP3
expression was knockdown, cyclin D1 protein slightly recovered in the stable
cell line. Even more, only the expression of the translation-deficient eIF4E
and normal eIF4E resulted in the increased protein level of cyclin D1, where
the same situation is not observed when RNA-transport-deficient eIF4E was
expressed. To conclude all above, the results suggested that the nuclear
eIF4E-mediated transportation of cyclin D1 mRNA was repressed by 4E-BP3,
and thus reduce the proliferation rate of the stably 4E-BP3 overexpressing
cells. Besides, we also examined whether the functions of 4E-BP3 are
affected with RPA2 overexpression, the result showed that RPA2 seemed to
further enhance the inhibition ability of 4E-BP3 in nucleus but not in cytosol.
The observation suggested that RPA2 may function as the transporter of the
4E-BP3 and thus affected the nucleo-cytoplasmic transportation of cyclin D1
mRNA.

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