在賓夕法尼亞州赫許的賓州州立大學(xué)醫(yī)學(xué)院的研究人員發(fā)現(xiàn)鴉片類生長因子(OGF, [Met5]-enkephalin)及它的受體, OGFr，不僅是臨床上有抗腫瘤潛力的重要系統(tǒng)，也控制細(xì)胞質(zhì)至核的傳送,，OGF-OGFr 由細(xì)胞質(zhì)傳送至細(xì)胞核在調(diào)控細(xì)胞生長上是關(guān)鍵的,，這也指出核的輸入有一個(gè)階層體系的調(diào)控。這發(fā)現(xiàn)將刊登在九月份《實(shí)驗(yàn)生物及醫(yī)學(xué)》(Experimental Biology and Medicine)期刊,，它不僅對我們探討和這基本生物系統(tǒng)相關(guān)疾病的病態(tài)生物機(jī)制提供新的看法,，也有助于發(fā)展更有效治療的新藥物。
之前的免疫組織化學(xué)及免疫電子顯微鏡的研究已發(fā)現(xiàn)OGF及OGFr分別位于細(xì)胞質(zhì)及細(xì)胞核,，OGF-OGFr 可以經(jīng)由調(diào)節(jié)細(xì)胞周期蛋白依賴激酶抑制劑,，造成細(xì)胞延遲在G1-S階段，而調(diào)控細(xì)胞的生長,。利用人類頭頸部鱗狀上皮腫瘤細(xì)胞株以及OGFr 接上綠色螢光蛋白質(zhì)的實(shí)驗(yàn),，發(fā)現(xiàn)一個(gè)輸送因子、karyopherin β,、在細(xì)胞質(zhì)核的傳送上扮演一個(gè)重要的角色,，karyopherin β 運(yùn)送至核需要GTPase Ran，如果用siRNA降低karyopherin β 及Ran,，但不是連結(jié)分子karyopherin β,，會阻止OGFr-eGFP的核傳送，進(jìn)而顯著增加DNA的合成,，這結(jié)果證明OGF-OGFr 軸調(diào)控細(xì)胞周期的方式是利用及時(shí)及正確地移轉(zhuǎn)這勝肽-受體復(fù)合物通過細(xì)胞核膜,，這細(xì)胞質(zhì)核的傳送對細(xì)胞生長是很關(guān)鍵的。
這研究團(tuán)隊(duì)是由神經(jīng)及行為科學(xué)系的杰出大學(xué)教授Ian S. Zagon博士,、教授Patricia J. McLaughlin博士,、及博士后研究員Fan Cheng博士組成，Zagon 及 McLaughlin博士發(fā)現(xiàn)內(nèi)生性的鴉片有調(diào)節(jié)細(xì)胞生長的特性,，鑒定特定的勝肽為OGF，選殖并定序OGFr,，他們和Cheng博士證明OGF經(jīng)由內(nèi)涵蛋白導(dǎo)引的胞吞作用進(jìn)入細(xì)胞質(zhì),，和OGFr 結(jié)合后經(jīng)由核安置區(qū)域傳送至細(xì)胞核，他們共同合作證明這原生的勝肽在很多的臨床研究扮演特殊的性質(zhì),。OGF已在胰臟癌第一期及第二期臨床試驗(yàn)證明成功,，在頭頸部鱗狀上皮癌也是安全有效，肝癌的試驗(yàn)正進(jìn)行中,。共同作者M(jìn)cLaughlin博士說明＂ 因?yàn)镺GF-OGFr 軸在調(diào)控細(xì)胞周期有多面性及細(xì)微的生物調(diào)節(jié),，可看成在細(xì)胞質(zhì)核的傳送上有減少或增加都會對疾病的發(fā)生及進(jìn)展帶來影響，這些蛋白質(zhì)被放在錯(cuò)誤的位置都會造成病態(tài)的狀態(tài),。＂Zagon博士補(bǔ)充說明＂ 這研究的臨床應(yīng)用是說,，OGF-OGFr 軸是身體調(diào)節(jié)生理過程的一個(gè)自我機(jī)制,，任何因子影響到它的細(xì)胞質(zhì)核的傳送都可以被應(yīng)用來治療人類疾病，增強(qiáng)這些因子可以有效地降低和細(xì)胞不正常生長有關(guān)的發(fā)炎,、自體免疫疾病,、及癌癥。＂
《實(shí)驗(yàn)生物及醫(yī)學(xué)》期刊主編Steven R. Goodman說 ＂Ian Zagon及其同事共同發(fā)現(xiàn)在人類健康及疾病上有無數(shù)作用的鴉片類生長因子(OGF)及它的受體(OGFr),，在這篇有趣的文章,，他們證明OGF-OGFr 進(jìn)入細(xì)胞核的分子機(jī)制，更特異地說,，他們證明karyopherin β 及Ran在過程中扮演的角色,，OGF-OGFr傳送至細(xì)胞核對調(diào)控細(xì)胞的生長是關(guān)鍵的。＂（生物谷Bioon.com）
生物谷推薦原文出處：
Exp.Biol.Med. doi:10.1258/ebm.2010.010139
Regulation of cell proliferation by the opioid growth factor receptor is dependent on karyopherin β and Ran for nucleocytoplasmic trafficking
Fan Cheng, Patricia J McLaughlin and Ian S Zagon
Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, H109, The Milton S Hershey Medical Center, 500 University Drive, Room C3729, Hershey, PA 17033, USA
The opioid growth factor (OGF; [Met5]-enkephalin) and the OGF receptor (OGFr) form an endogenous and tonically active growth-regulating system that modulates cell proliferation by upregulating the cyclin-dependent kinase inhibitory pathway. Previous reports have documented that nucleocytoplasmic trafficking of the OGF–OGFr axis is dependent on nuclear localization signals. This study determined the specific transport factors required for the import of the OGF–OGFr complex from the cytoplasm to the nucleus using a probe of full-length OGFr fused to enhanced green fluorescent protein (eGFP) and knockdown of karyopherin 1, 2, 3, 4 or 6, karyopherin β1 or Ran with small interfering RNA (siRNA). A human squamous cell carcinoma of the head and neck cell line (squamous cell carcinoma-1, SCC-1) that was downregulated for karyopherin β1 or Ran did not have transport of OGFr-eGFP into the nucleus. Moreover, there was an increase of 44% in bromodeoxyuridine (BrdU)-labeled cells in cultures of SCC-1 that were transfected with siRNAs to karyopherin β1 or Ran compared with cells transfected with scrambled siRNA. No alteration in distribution of OGFr-eGFP or BrdU labeling indexes was recorded in cultures treated with siRNAs to karyopherin 1, 2, 3, 4 or 6. These results indicate that the regulation of cell proliferation by the OGF–OGFr axis is dependent on nucleocytoplasmic transport by karyopherin β1 as well as the gradient of RanGTP/RanGDP across the nuclear envelope, but is not reliant on adaptor molecules related to karyopherin . Thus, the passage of the OGF–OGFr complex has controlled entry from the cytoplasm to the nucleus, and the timely and faithful translocation of this cargo across the nuclear envelope is critical to cell proliferation. These hierarchical levels of nuclear import provide multiple pathways for the subtle regulation of OGF–OGFr as it relates to the control of cell proliferative events.
