位于美國賓卅Hershey的賓州州立大學醫(yī)學院的研究人員發(fā)現(xiàn)鴉片生長因子(OGF, [Met5]-enkephalin),，一個臨床上重要的抗腫瘤試劑，其有效的作用是決定于它受體OGFr的細胞核置訊號(NLS)能否將受體送入細胞核內(nèi),，此研究結(jié)果會刊登在實驗生物及醫(yī)學2009年五月份的期刊上，它對我們了解一個重要的內(nèi)生性系統(tǒng)的機制提供一個新的看法,，這系統(tǒng)是增強性且固定性的表現(xiàn)可以抑制性調(diào)節(jié)DNA的合成,。這重要的信息不僅幫助我們了解OGF-OGFr生物系統(tǒng)在一些有關(guān)疾病的發(fā)生及致病角色，也有助于研發(fā)可以增強治療效果的新藥物,。
之前的免疫組織化學及電子顯微鏡的研究在細胞質(zhì)及細胞核都發(fā)現(xiàn)有OGF及OGFr,，而OGF-OGFr軸心已知調(diào)節(jié)細胞的增殖是透過影響細胞周期素依賴激酶的抑制劑，造成細胞周期停留在G1-S階段,。為探討OGFr在細胞內(nèi)運送的過程,，合成一個OGFr和綠色螢光蛋白質(zhì)(eGFP) 的復合物，追蹤在人類頭頸部鱗狀癌細胞的運送,，發(fā)現(xiàn)OGFr的轉(zhuǎn)譯合成須5小時,，輸送至細胞核須8小時，之后可以停留在細胞核達8天,。送至細胞核孔及抑制細胞的增殖須要OGFr三個細胞核置訊號(NLS) 中的二個,。這結(jié)果顯示OGF-OGFr復合物參與調(diào)節(jié)細胞周期的路徑是透過勝肽-受體復合物從細胞質(zhì)內(nèi)運送至細胞核以及運輸?shù)氖荏w。
這研究團隊是由神經(jīng)及行為科學系杰出教授Dr. Ian S. Zagon,、教授Dr. Patricia J. McLaughlin,、及博士后研究Dr. Fan Cheng組成，Drs. Zagon 及McLaughlin發(fā)現(xiàn)內(nèi)生系的鴉片似的物質(zhì)具調(diào)節(jié)生長的功能,，鑒定OGF是特異的勝肽,，選殖及定序OGFr，共同合作證明這些天然的勝肽在很多臨床的研究都有很大的作用,，OGF在臨床第一期試驗已證明是成功的,，治療胰臟癌及頭頸部的鱗狀細胞癌的臨床第二期試驗正在進行中。第二作者Dr. McLaughlin說＂透過OGF-OGRr軸心特殊的生物調(diào)控細胞周期,，可以預期如果它的輸送系統(tǒng)有損失或增強都會對疾病的發(fā)生及進展帶來影響＂ ,。Dr. Zagon補充說＂ 這研究的臨床意義是OGF-OGFr軸心的細胞質(zhì)核的運送有任何改變，可以是來自自己身體的生理作用,，都有可能參與人類疾病的發(fā)生及致病機轉(zhuǎn),，也構(gòu)成治療疾病的基礎(chǔ)＂。
Experimental Biology and Medicine 期刊總編輯Dr. Steven R. Goodman也說＂Zagon及其同事發(fā)現(xiàn)鴉片生長因子(OGF, [Met5]-enkephalin),，一個臨床上重要的抗腫瘤試劑,，的作用決定于勝肽及其OGF受體從細胞質(zhì)送入細胞核，這發(fā)現(xiàn)可能提供我們了解這個天然生物系統(tǒng)在相關(guān)疾病發(fā)生及致病機制上很重要的訊息,，也有助于發(fā)展增強治療效果的新藥物＂,。（生物谷Bioon.com）
生物谷推薦原始出處：
Experimental Biology and Medicine doi: 10.3181/0901-RM-16
Dependence on Nuclear Localization Signals of the Opioid Growth Factor Receptor (OGFr) in the Regulation of Cell Proliferation
Fan Cheng 1, Patricia J. McLaughlin 2, Michael F. Verderame 1, and Ian S. Zagon 1*
1 Pennsylvania State Univ
2 The Pennsylvania State Univesity College of Medicine
The opioid growth factor receptor (OGFr) mediates the inhibitory action of OGF on cell replication of normal and neoplastic cells. The spatiotemporal course of OGFr nucleocytoplasmic trafficking was determined with a probe of full-length OGFr fused to green fluorescent protein (eGFP). Translation of OGFr required 5.5 hours, and transit into the nucleus required 8 hours; OGFr remained in the nucleus for 8 days. OGFr was initially expressed on the outer nuclear envelope, transited to the paranuclear cytoplasm, and into the nucleus. Transport through the nuclear pore was elucidated by mutation of the nuclear localization sequences (NLS) in full-length OGFr. Mutation of each NLS reduced nuclear localization by 5-50%, whereas simultaneous mutation of NLS383-386 and NLS456-460 abolished eGFP-OGFr nuclear localization in 80% of the cells. To determine whether intact NLSs are important for the inhibition of cell proliferation, DNA synthesis was monitored with BrdU. Wild-type eGFP-OGFr transfected cells had 20% BrdU positive cells, whereas cells with simultaneous mutation of all three NLS sites had a 70% labeling index. These results indicate that the regulation of cell proliferation by the OGF-OGFr axis is dependent on nucleocytoplasmic translocation, and reliant on the integrity of two NLSs in OGFr to interact with transport receptors.
