原癌基因人類(lèi)表皮生長(zhǎng)因子受體2（HER-2）一般在癌細(xì)胞內(nèi)過(guò)量表達(dá),，但是其機(jī)制目前仍不明確,。近日,，來(lái)自夏威夷大學(xué)的研究人員Scott K. Kuwada等人表示，癌細(xì)胞內(nèi)非典型組蛋白macroH2A1.2與HER-2的相互作用能夠促進(jìn)原癌基因的表達(dá)及細(xì)胞增生,。
研究發(fā)現(xiàn),，在HER-2過(guò)表達(dá)的癌細(xì)胞內(nèi)，非典型組蛋白macroH2A1能夠與HER-2相互作用,。人類(lèi)mH2A1具有兩種亞型,，mH2A1.2與mH2A1.1。在人癌細(xì)胞系,，他們發(fā)現(xiàn)mH2A1.2而不是mH2A1.1,，能夠與HER-2相互作用。
在致瘤性及HER-2表達(dá)顯著提高的癌細(xì)胞,，他們發(fā)現(xiàn)mH2A1.2表現(xiàn)出過(guò)表達(dá)水平,。在癌細(xì)胞，抑制HER-2激酶活性,，削弱了mH2A1的表達(dá),，降低了mH2A1.2誘導(dǎo)的原癌基因ERBB2的轉(zhuǎn)錄。
在穩(wěn)定轉(zhuǎn)染mH2A1.2的癌細(xì)胞,，染色質(zhì)免疫共沉淀實(shí)驗(yàn)顯示,，mH2A1.2富集在HER-2的啟動(dòng)子，這表明mH2A1.2具有促進(jìn)HER-2過(guò)表達(dá)的作用,。
進(jìn)一步研究表明，進(jìn)化上保守的mH2A1.2的宏結(jié)構(gòu)域（macro domain）,，對(duì)于HER-2與mH2A1.2的相互作用及mH2A1.2誘導(dǎo)的ERBB2的轉(zhuǎn)錄十分必要,。
有趣的是，mH2A1.2的宏結(jié)構(gòu)域具有mH2A1.1沒(méi)有的三核苷酸的插入序列,，它可能對(duì)HER-2與mH2A1.2的相互作用,，對(duì)mH2A1.2誘導(dǎo)的ERBB2轉(zhuǎn)錄及細(xì)胞增生是必不可少的。
Scott K. Kuwada表示,，本次發(fā)現(xiàn)闡明了mH2A1.2與HER-2之間新的相互作用機(jī)制,，表明了一個(gè)獨(dú)特的機(jī)制，即原癌基因能夠廣泛的引起癌細(xì)胞內(nèi)基因轉(zhuǎn)錄失調(diào),。（生物谷Deepblue編譯）
doi: 10.1074/jbc.M112.379412
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PMID:
The atypical histone macroH2A1.2 interacts with HER-2 in cancer cells
Xiufen Li, Jinqui Kuang, Yi Shen, Martin M. Majer, Chad C. Nelson, Krishna Parsawar, Karen A. Heichman and Scott K. Kuwada
Since HER-2 has been demonstrated in the nuclei of cancer cells we hypothesized that it might interact with transcription factors that activate ERBB2 transcription.macroHistone 2A1 (H2AFY; mH2A1) was found to interact with HER-2 in cancer cells that overexpress HER-2. Of the two human mH2A1 isoforms, mH2A1.2, but not mH2A1.1, interacted with HER-2 in human cancer cell lines.Overexpression of mH2A1.2, but not mH2A1.1, in cancer cells significantly increased HER-2 expression and tumorigenicity. Inhibition of HER-2 kinase activity diminished mH2A1 expression and mH2A1.2-induced ERBB2 transcription in cancer cells.Chromatin immunoprecipitation of mH2A1.2 in cancer cells stably transfected with mH2A1.2 showed enrichment of mH2A1.2 at the HER-2 promoter suggesting a role for mH2A1.2 in driving HER-2 overexpression.The evolutionarily conserved macro domain of mH2A1.2 was sufficient for the interaction between HER-2 and mH2A1.2, and, for mH2A1.2-induced ERBB2 transcription.Within the macro domain of mH2A1.2, a trinucleotide insertion (-eis) sequence not found in mH2A1.1 was essential for the interaction between HER-2 and mH2A1.2 as well as mH2A1.2-induced HER-2 expression and cell proliferation.
