The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1
The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1
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DOI：
10.1038/sj.onc.1207497
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发表时间：
2004-05-06
期刊：
影响因子：
8
通讯作者：
Latchman, DS
中科院分区：
文献类型：
--
作者：
Gascoyne, DM;Thomas, GR;Latchman, DS
BRN-3家族的POU(Pit-Oct-UNC)同源结构域转录因子调节神经细胞类型的分化。转录激活子BRN-3a在尤文氏肉瘤中表达，由于Tet家族基因EWS与几个ETS基因之一的融合，该肉瘤也表达特有的嵌合蛋白。我们先前已经证明了BRN-3a和EWS蛋白之间的物理相互作用，并在这里表明BRN-3a的C端POU结构域而不是N端激活结构域在体外可以与EWS的RNA结合域相互作用。可能由于POU结构域的同源性，相关因子BRN-3b也可以与EWS相互作用，但程度低于BRN-3a。重要的是，BRN-3a而不是BRN-3b在体外与嵌合的EWS/Fli-1、EWS/ATF-1和EWS/ERG蛋白相互作用。此外，EWS/Fli-1的过表达而不是EWS或Fli-1的过表达抑制了BRN-3a相关的神经细胞生长停滞和突起生长，并特异性地抑制了依赖BRN-3a的p21和SNAP-25转录的激活。相反，EWS比EWS/Fli-1更能拮抗BRN-3a上调Bcl2表达和抑制细胞凋亡的作用。这些数据表明，EWS的致癌重排产生EWS/Fli-1可能会增强BRN-3a的抗凋亡作用，并抑制其促进神经元分化的能力。
The Brn-3 family of POU (Pit-Oct-Unc) homeodomain transcription factors regulate differentiation of neuronal cell types. The transcriptional activator Brn-3a is expressed in Ewing's sarcomas, which also express characteristic chimaeric proteins as a consequence of fusion of the TET family gene EWS to one of several ETS genes. We have previously demonstrated a physical interaction between Brn-3a and EWS proteins, and show here that the C-terminal POU domain but not N-terminal activation domain of Brn-3a can interact in vitro with the RNA-binding domain of EWS. Likely due to POU domain homology, the related factor Brn-3b can also interact with EWS, but to a lesser extent than Brn-3a. Importantly, Brn-3a but not Brn-3b interacts in vitro with chimaeric EWS/Fli-1, EWS/ATF-1 and EWS/ERG proteins. Furthermore, overexpression of EWS/Fli-1 but not EWS or Fli-1 inhibits Brn-3a-associated growth arrest and neurite outgrowth in neuronal cells, and specifically inhibits Brn-3a-dependent activation of p21 and SNAP-25 transcription. In contrast, upregulation of Bcl-2 expression and inhibition of apoptosis by Brn-3a is antagonized more by EWS than by EWS/Fli-1. These data demonstrate that oncogenic rearrangement of EWS to produce EWS/Fli-1 may enhance the antiapoptotic effect of Brn-3a and inhibit its ability to promote neuronal differentiation.