H4組織蛋白上之酪胺酸磷酸化於癌症發展中的角色探討

中國醫藥大學機構典藏 China Medical University Repository, Taiwan > 台中附設醫院 > 研究計畫 > Item 310903500/47673

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题名:	H4組織蛋白上之酪胺酸磷酸化於癌症發展中的角色探討 Roles of Tyrosine Phosphorylation on Histone H4 in Cancer Progression
作者:	鄒瑞煌(Ruey-Hwang Chou)
贡献者:	醫學院癌症生物學研究所;中國附醫分子醫學中心-分子細胞生物學
关键词:	?胺酸磷酸化;H4 組織蛋白;癌症發展;癌症治?;tyrosine phosphorylation;histone H4;cancer progression;cancer therapy
日期:	2013-07-31
上传时间:	2013-01-25 13:44:32 (UTC+8)
摘要:	組織蛋白的轉譯後修飾包含乙醯化、甲基化、磷酸化和泛素化等於染色質的動態與功能扮演著重要的角色。雖然許多組織蛋白上的磷酸化已被發現，但絕大多?是在絲胺酸與蘇胺酸上。織蛋白上的?胺酸磷酸化還很少被研究。於本研究中，我們發現H4組織蛋白上的?個新穎?胺酸磷酸化位點在Y51與Y72上。我們初步證明屬於受器?胺酸激? （RTK）之一的上皮生長因子受器（EGFR），它高?表現於許多癌症，能與H4組織蛋白相互作用並進?磷酸化。我們的初步結果顯示Y51與Y72的磷酸化分別會影響其K5的乙醯化與K20的甲基化，而這?個轉譯後修飾分別?與轉?活化與DNA合成和修補。此外，H4組織蛋白上的Y72磷酸化程?於癌化細胞株中明顯高於正常細胞株。我們假設H4 組織蛋白上的Y72磷酸化可能與癌症發展相關。因此，於本研究計畫中，我們將研究H4 組織蛋白上Y51與Y72的調控機制與生物功能和它們於癌症發展中所扮演的角色。為此目的，我們出四個主要研究目標：（1）研究H4組織蛋白上?胺酸磷酸化在其轉譯後修飾的調控；（2）找出H4組織蛋白上Y51與Y72磷酸化的可能生物功能；（3）研究H4組織蛋白上Y51與Y72磷酸化於癌症?化的影響；（4）?用H4組織蛋白Y51與Y72的衍生胜?或合併?床上的EGFR抑制劑用藥（如：Iressa或Tarceva）發展具潛?的癌症治?策?。完成此研究計畫將能提供?多知?關於H4組織蛋白磷酸化於DNA合成、修補與轉?調控以及癌症發展的功能。這將可能對於?用標靶抑制H4組織蛋白磷酸化所?與的生物功能發展新穎癌症治?策?有所貢獻。經由本研究經費的支持，我們將訓?4至5個研究生，使其未?能具備生醫研究或生物技術?域的相關能?。 Post-translational modifications (PTMs) of histones including acetylation, methylation, phosphorylation, and ubiquitination, play important roles in chromatin dynamics and functions. Although many phosphorylated modifications on histones have been identified, most of them occurred on serine or threonine residues. It is rarely understood about tyrosine phosphorylation on histones. In the current study, we identified two novel tyrosine phosphorylation sites at Y51 and Y72 on histone H4. We also demonstrated that a receptor tyrosine kinase (RTK), epidermal growth factor receptor (EGFR), which overexpresses in several cancers, could interact with and phosphorylate histone H4. Our preliminary results revealed that phosphorylation at Y51 and Y72 on histone H4 affects its K5 acetylation and K20 methylation, respectively, which are involved in transcriptional activation, DNA synthesis and repair. Moreover, histone H4-Y72 phosphorylation is much higher in cancerous cell lines than that in normal cell lines, suggesting tyrosine phosphorylation might be related to cancer progression. Thus, in the proposal, we will investigate the regulatory mechanism and biological function of histone H4-Y51 and H4-Y72 phosphorylation, and their roles cancer progression. To these ends, four specific aims are proposed: (1) to study the regulation of PTMs on histone H4 by tyrosine phosphorylation; (2) to characterize the biological functions of phosphorylation at Y51 and Y72 on histone H4; (3) to investigate the effects of phosphorylation at histone H4-Y51 and H4-Y72 on cancer malignancy; (4) to develop the potential cancer therapeutic strategy by treatment of the histone H4-Y51 and H4-Y72 derived peptides and combination treatment with clinical used TKIs of EGFR, such as Iressa or Tarceva. Achievement of the proposal will provide more knowledge on tyrosine phosphorylation of histone H4 in several biological functions including DNA synthesis, repair, transcriptional regulation, as well as in cancer progression. That might contribute to develop a novel cancer therapeutic strategy that target to tyrosine phosphorylated histone H4 mediated cellular functions. With the grant support, we will train 4-5 graduate students to be capable of biomedical and biotechnological research.
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