Thirkettle H J, Mills I G, Whitaker H C, Neal D E
Uro-Oncology Research Group, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
Oncogene. 2009 Oct 15;28(41):3663-70. doi: 10.1038/onc.2009.223. Epub 2009 Aug 3.
LYRIC/AEG-1 and its altered expression have been linked to carcinogenesis in prostate, brain and melanoma as well as promoting chemoresistance and metastasis in breast cancer. LYRIC/AEG-1 function remains unclear, although LYRIC/AEG-1 is activated by oncogenic HA-RAS, through binding of c-myc to its promoter, which in turn regulates the key components of the PI3-kinase and nuclear factor-kappaB pathways. We have identified the transcriptional repressor PLZF as an interacting protein of LYRIC/AEG through a yeast two-hybrid screen. PLZF regulates the expression of genes involved in cell growth and apoptosis including c-myc. Coexpression of LYRIC/AEG-1 with PLZF leads to a reduction in PLZF-mediated repression by reducing PLZF binding to promoters. We have confirmed that nuclear LYRIC/AEG-1 and PLZF interact in mammalian cells via the N- and C termini of LYRIC/AEG-1 and a region C terminal to the RD2 domain of PLZF. Both proteins colocalize to nuclear bodies containing histone deacetylases, which are known to promote PLZF-mediated repression. Our data suggest one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression.
LYRIC/AEG-1及其表达改变与前列腺癌、脑癌和黑色素瘤的致癌作用有关，还与乳腺癌的化疗耐药性和转移相关。尽管LYRIC/AEG-1可被致癌性HA-RAS激活，通过c-myc与其启动子结合，进而调节PI3激酶和核因子-κB通路的关键成分，但LYRIC/AEG-1的功能仍不清楚。我们通过酵母双杂交筛选鉴定出转录抑制因子PLZF是LYRIC/AEG的相互作用蛋白。PLZF调节包括c-myc在内的参与细胞生长和凋亡的基因表达。LYRIC/AEG-1与PLZF共表达会通过减少PLZF与启动子的结合导致PLZF介导的抑制作用减弱。我们已证实，在哺乳动物细胞中，核内的LYRIC/AEG-1与PLZF通过LYRIC/AEG-1的N端和C端以及PLZF的RD2结构域C端的一个区域相互作用。这两种蛋白共定位于含有组蛋白脱乙酰酶的核体，已知这些核体会促进PLZF介导的抑制作用。我们的数据表明，LYRIC/AEG-1表达改变的细胞在肿瘤发生过程中通过调节PLZF抑制作用来逃避凋亡并增加细胞生长的一种机制。
