Nakagawa Takahito, Takahashi Masato, Ozaki Toshinori, Watanabe Ken-ichi, Hayashi Shunji, Hosoda Mitsuchika, Todo Satoru, Nakagawara Akira
Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Cancer Lett. 2003 Jul 18;197(1-2):105-9. doi: 10.1016/s0304-3835(03)00090-9.
p73, mapped to 1p36.2-3, is a p53-related tumor suppressor but is also induced by the oncogene products such as E2F1, raising a question whether p73 is a tumor suppressor gene or oncogene. p73 has several splicing variants including DeltaNp73 which lacks the NH(2)-terminal transactivation domain. In developing neurons, DeltaNp73 is expressed abundantly and seems to inhibit the pro-apoptotic function of p53. However, the role of TAp73 and DeltaNp73 as well as their regulatory mechanism in cell growth and differentiation of neuroblastoma cells are poorly understood. We have found that TAp73 directly activates the transcription of endogenous DeltaNp73 by binding to the TAp73-specific target element located at position-76 to 57 within the DeltaNp73 promoter region. DeltaNp73 was physically associated with TAp73alpha, TAp73beta and p53, and inhibited their transactivation activities when used reporters of Mdm2, Bax or DeltaNp73 itself in SAOS-2 cells. Overexpression of DeltaNp73 in SH-SY5Y neuroblastoma cells promoted cell survival by competing with p53 and TAp73 itself. Thus, our results suggest that the negative feedback regulation of TAp73 by its target DeltaNp73 is a novel autoregulatory system for modulating cell survival and death, that is also functioning in neuroblastoma cells.
p73基因定位于1p36.2 - 3，是一种与p53相关的肿瘤抑制因子，但也可由E2F1等癌基因产物诱导产生，这就引发了一个问题，即p73是肿瘤抑制基因还是癌基因。p73有多种剪接变体，包括缺少NH(2)-末端反式激活结构域的DeltaNp73。在发育中的神经元中，DeltaNp73大量表达，似乎能抑制p53的促凋亡功能。然而，TAp73和DeltaNp73在神经母细胞瘤细胞的生长和分化中的作用及其调控机制仍知之甚少。我们发现，TAp73通过与位于DeltaNp73启动子区域-76至57位的TAp73特异性靶元件结合，直接激活内源性DeltaNp73的转录。在SAOS-2细胞中，当使用Mdm2、Bax或DeltaNp73自身的报告基因时，DeltaNp73与TAp73α、TAp73β和p53发生物理相互作用，并抑制它们的反式激活活性。在SH-SY5Y神经母细胞瘤细胞中过表达DeltaNp73，通过与p53和TAp73自身竞争，促进细胞存活。因此，我们的结果表明，TAp73被其靶标DeltaNp73的负反馈调节是一种调节细胞存活和死亡的新型自动调节系统，该系统也在神经母细胞瘤细胞中发挥作用。
