The unique NH2-terminally deleted (ΔN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the ΔN variant of p63
The unique NH2-terminally deleted (ΔN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the ΔN variant of p63
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DOI：
10.1074/jbc.m507964200
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发表时间：
2006-02-03
影响因子：
4.8
通讯作者：
Chen, XB
中科院分区：
文献类型：
--
作者：
Helton, ES;Zhu, JH;Chen, XB
p63是转录因子p53家族的成员，已知其参与上皮发育。然而，其在肿瘤发生中的作用尚不清楚。TP 63基因座可以从两个不同的启动子表达多个基因产物，这也导致了这种不确定性。上游启动子的利用导致具有类似于p53的激活结构域的TAp 63变体的表达。相比之下，NH 2-末端缺失的（Delta N）p63变体，从内含子3中的隐蔽启动子转录，缺乏这样的激活结构域。因此，TAp 63和Δ Np 63变体具有广泛的上调p53靶基因的能力。因此，p63变体之间反式激活潜力的差异引起了这样的假设，即Δ Np 63变体可以通过对抗TAp 63变体和p53的活性而作为癌蛋白。然而，最近的研究揭示了Delta Np 63的转录活性。进行本研究以解决Delta Np 63变体的转录活性。在这里，我们表明，所有的NH 2-末端删除p63亚型保留了潜在的反式激活和生长抑制。有趣的是，Delta Np 63 β具有显著的抑制细胞增殖和反式激活靶基因的能力，其始终高于Delta Np 63 α。相反，Delta Np 63 γ具有弱的或不可检测的活性，这取决于所使用的细胞系。我们还表明，一个完整的DNA结合结构域所需的三角洲Np 63功能。此外，我们发现Delta Np 63变体的新激活结构域由14个独特的Delta N残基沿着与相邻区域组成，包括PXXP基序。最后，我们证明了由Delta Np 63 α和Delta Np 63 β共享的PPXY基序是靶基因启动子的最佳反式激活所必需的，这表明PPXY基序是Delta Np 63功能所必需的。
p63, a member of the p53 family of transcription factors, is known to be involved in epithelial development. However, its role in tumorigenesis is unclear. Contributing to this uncertainty, the TP63 locus can express multiple gene products from two different promoters. Utilization of the upstream promoter results in expression of the TAp63 variant with an activation domain similar to p53. In contrast, the NH2-terminally deleted (Delta N) p63 variant, transcribed from a cryptic promoter in intron 3, lacks such an activation domain. Thus, the TAp63 and Delta Np63 variants possess a wide ranging ability to up-regulate p53 target genes. Consequentially, the disparity in transactivation potential between p63 variants has given rise to the hypothesis that the Delta Np63 variant can serve as oncoprotein by opposing the activity of the TAp63 variant and p53. However, recent studies have revealed a transcriptional activity for Delta Np63. This study was undertaken to address the transcriptional activity of the Delta Np63 variant. Here, we showed that all NH2-terminally deleted p63 isoforms retain a potential in transactivation and growth suppression. Interestingly, Delta Np63 beta possesses a remarkable ability to suppress cell proliferation and transactivate target genes, which is consistently higher than that seen with Delta Np63 alpha. In contrast, Delta Np63 gamma has a weak or undetectable activity dependent upon the cell lines used. We also demonstrate that an intact DNA-binding domain is required for Delta Np63 function. In addition, we found that the novel activation domain for the Delta Np63 variant is composed of the 14 unique Delta N residues along with the adjacent region, including a PXXP motif. Finally, we demonstrated that a PPXY motif shared by Delta Np63 alpha and Delta Np63 beta is required for optimal transactivation of target gene promoters, suggesting that the PPXY motif is requisite for Delta Np63 function.