轉錄因子

轉錄因子 YY1 對於調控 Notch2 訊息傳遞路 徑之探討

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（ apoptosis ）上扮演著極為關鍵的角色。不正常之 Notch 訊息傳遞會造成發育過程失 調、神經退化疾病以及細胞癌化現象，例如：急性 T 細胞母淋巴球白血病（ T-cell acut e lymphoblastic leukemia ； T-ALL ）及子宮頸癌等。另外， Notch 之功能除了可當作一 致癌基因外，最近也有文獻指出其可當作一腫瘤抑制劑。

在哺乳類動物中所鑑定出之 Notch 受體有四種（ Notch1-4 ），其中以 Notch1 與 Notch2 間之相似度為最高。對於 Notch 訊息傳遞之機制而言，主要分為二種：一為常見的 CS L-dependent 路徑；另一則是 CSL-independent 路徑，前者主要是在 Notch 與其 ligand 結 合後，會誘導出一連串蛋白水解反應而產生活化態之 Notch intracellular domain （ NI C ），接著 NIC 會進一步地從細胞質轉移至細胞核內，並結合於轉錄因子 CSL response element 上，再與一些 coactivators 形成一高分子之複合體來活化下游標的基因之表現；

而對於後者之主要機制至今仍未被清楚地闡明。

本論文擬以探討轉錄因子 YY1 是否會透過與 Notch2 intracellular domain （ N2IC ）之結 合，而調控 CBF1-dependent 之 Notch2 訊息傳遞路徑。本論文研究發現內生性之 Notch2 蛋白會表現於 K562 與 HeLa 細胞株中。另外，本論文也證實在於 HeLa 細胞中，內生 性 N2IC 與 YY1 間可能有結合之關係存在。且當 YY1 大量表現於 K562 細胞時，發現 其對於 CBF1-dependent 之 Notch2 訊息傳遞所活化之 luciferase 報導基因活性會有抑制 作用。除此之外， YY1 所間接調控 wild-type CBF1-response element 之轉錄活性則是透 過 N2IC 與 CBF1 間之直接結合關係而造成。綜合以上之研究結果，轉錄因子 YY1 可能 會透過與 N2IC 相互結合而調節 Notch2 之訊息傳遞路徑。

Studies of the transcription factor YY1 in the regulation of Notch2 signaling

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Notch signaling pathway plays a key role in proliferation, differentiation and apoptosis. Aberrant Notch sig naling is associated with several developmental disorders, neurodegenerative disease and cancers, includin g acute T-cell lymphoblastic leukemia (T-ALL) and cervical cancer. Notch has two faces: one that can be a s an oncogene, which promotes tumorigenesis and the other that can be a tumor suppressor, which suppress es tumorigenesis.

In mammalian, four Notch homologues (Notch1-4) have been identified. The Notch signal pathway can be activated through both CSL-dependent and -independent pathways. After binding of ligands, Notch is clea vaged by a series of proteases to release Notch intracellular domain (NIC). The NIC translocates into the n ucleus to bind with the transcription factor C promoter bonding factor-1 (CBF1)/Recombination signal bin ding protein (RBP-Jκ), Suppressor of Hairless 〔 Su (H) 〕 or Lag-1 (CSL), and then recruits some co-ac tivators to activate the expressions of downstream target genes. At present, the mechanism of the CSL-inde pendent pathway is still unknown.

Recently, Yeh et al. demonstrated that transcription factor Yin-Yang 1 (YY1) regulates Notch1 signaling vi

a the association with the high molecular weight Notch complex. However, it is still unknown, whether the

YY1 also modulate Notch2 signaling. Here, it was shown that the endogenous Notch2 intracellular domain

(N2IC) was expressed in K562 and HeLa cells. The endogenous N2IC was associated with intrinsic YY1 i

n HeLa cells. Exogenous expression of YY1 in K562 cells, the CBF1-dependent luciferase reporter activity

transactivated by Notch2 signaling was suppressed. Besides, the transcription factor YY1 regulated the CB

F1-dependent transcriptional activity indirectly. Taken together, these results suggested that transcription f

actor YY1 might modulate Notch2 signaling through the interaction with N2IC.