Gagrica Sladjana, Hauser Stefanie, Kolfschoten Ingrid, Osterloh Lisa, Agami Reuven, Gaubatz Stefan
Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Marburg, Germany.
EMBO J. 2004 Nov 24;23(23):4627-38. doi: 10.1038/sj.emboj.7600470. Epub 2004 Nov 11.
Genetic studies in Caenorhabditis elegans identified lin-9 to function together with the retinoblastoma homologue lin-35 in vulva differentiation. We have now identified a human homologue of Lin-9 (hLin-9) and provide evidence about its function in the mammalian pRB pathway. hLin-9 binds to pRB and cooperates with pRB in flat cell formation in Saos-2 cells. In addition, hLin-9 synergized with pRB and Cbfal to transactivate an osteoblast-specific reporter gene. In contrast, hLin-9 was not involved in pRB-mediated inhibition of cell cycle progression or repression of E2F-dependent transactivation. Consistent with these data, hLin-9 was able to associate with partially penetrant pRB mutants that do not bind to E2F, but retain the ability to activate transcription and to promote differentiation. hLin-9 can also inhibit oncogenic transformation, dependent on the presence of a functional pRB protein. RNAi-mediated knockdown of Lin-9 can substitute for the loss of pRB in transformation of human primary fibroblasts. These data suggest that hLin-9 has tumor-suppressing activities and that the ability of hLin-9 to inhibit transformation is mediated through its association with pRB.
对秀丽隐杆线虫的遗传学研究表明，lin-9与视网膜母细胞瘤同源物lin-35共同参与外阴分化过程。我们现已鉴定出Lin-9的人类同源物（hLin-9），并提供了其在哺乳动物pRB通路中功能的证据。hLin-9与pRB结合，并在Saos-2细胞的扁平细胞形成过程中与pRB协同作用。此外，hLin-9与pRB和Cbfal协同激活成骨细胞特异性报告基因。相反，hLin-9不参与pRB介导的细胞周期进程抑制或E2F依赖性反式激活的抑制。与这些数据一致，hLin-9能够与部分具有穿透性的不与E2F结合但保留激活转录和促进分化能力的pRB突变体结合。hLin-9还能够抑制致癌转化，这取决于功能性pRB蛋白的存在。RNAi介导的Lin-9敲低可替代人原代成纤维细胞转化中pRB的缺失。这些数据表明hLin-9具有肿瘤抑制活性，且hLin-9抑制转化的能力是通过其与pRB的结合介导的。
