在宾夕法尼亚州赫许的宾州州立大学医学院的研究人员发现鸦片类生长因子(OGF, [Met5]-enkephalin)及它的受体, OGFr，不仅是临床上有抗肿瘤潜力的重要系统，也控制细胞质至核的传送，OGF-OGFr 由细胞质传送至细胞核在调控细胞生长上是关键的，这也指出核的输入有一个阶层体系的调控。这发现将刊登在九月份《实验生物及医学》(Experimental Biology and Medicine)期刊，它不仅对我们探讨和这基本生物系统相关疾病的病态生物机制提供新的看法，也有助于发展更有效治疗的新药物。
之前的免疫组织化学及免疫电子显微镜的研究已发现OGF及OGFr分别位于细胞质及细胞核，OGF-OGFr 可以经由调节细胞周期蛋白依赖激酶抑制剂，造成细胞延迟在G1-S阶段，而调控细胞的生长。利用人类头颈部鳞状上皮肿瘤细胞株以及OGFr 接上绿色萤光蛋白质的实验，发现一个输送因子、karyopherin β、在细胞质核的传送上扮演一个重要的角色，karyopherin β 运送至核需要GTPase Ran，如果用siRNA降低karyopherin β 及Ran，但不是连结分子karyopherin β，会阻止OGFr-eGFP的核传送，进而显着增加DNA的合成，这结果证明OGF-OGFr 轴调控细胞周期的方式是利用及时及正确地移转这胜肽-受体复合物通过细胞核膜，这细胞质核的传送对细胞生长是很关键的。
这研究团队是由神经及行为科学系的杰出大学教授Ian S. Zagon博士、教授Patricia J. McLaughlin博士、及博士后研究员Fan Cheng博士组成，Zagon 及 McLaughlin博士发现内生性的鸦片有调节细胞生长的特性，鉴定特定的胜肽为OGF，选殖并定序OGFr，他们和Cheng博士证明OGF经由内涵蛋白导引的胞吞作用进入细胞质，和OGFr 结合后经由核安置区域传送至细胞核，他们共同合作证明这原生的胜肽在很多的临床研究扮演特殊的性质。OGF已在胰脏癌第一期及第二期临床试验证明成功，在头颈部鳞状上皮癌也是安全有效，肝癌的试验正进行中。共同作者McLaughlin博士说明＂ 因为OGF-OGFr 轴在调控细胞周期有多面性及细微的生物调节，可看成在细胞质核的传送上有减少或增加都会对疾病的发生及进展带来影响，这些蛋白质被放在错误的位置都会造成病态的状态。＂Zagon博士补充说明＂ 这研究的临床应用是说，OGF-OGFr 轴是身体调节生理过程的一个自我机制，任何因子影响到它的细胞质核的传送都可以被应用来治疗人类疾病，增强这些因子可以有效地降低和细胞不正常生长有关的发炎、自体免疫疾病、及癌症。＂
《实验生物及医学》期刊主编Steven R. Goodman说 ＂Ian Zagon及其同事共同发现在人类健康及疾病上有无数作用的鸦片类生长因子(OGF)及它的受体(OGFr)，在这篇有趣的文章，他们证明OGF-OGFr 进入细胞核的分子机制，更特异地说，他们证明karyopherin β 及Ran在过程中扮演的角色，OGF-OGFr传送至细胞核对调控细胞的生长是关键的。＂（生物谷Bioon.com）
生物谷推荐原文出处：
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.
