Amin A R M Ruhul, Paul Rajib K, Thakur Vijay S, Agarwal Munna L
Department of Genetics and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Cancer Res. 2007 Jun 15;67(12):5617-21. doi: 10.1158/0008-5472.CAN-07-0655.
Virtually all human cancers encounter disruption of the "p53 network." From a therapeutic point of view, it is important to devise strategies that eliminate cancer cells, which are often defective in functional p53 and protect p53-expressing normal cells. By comparing the response of a pair of isogenic cell lines, we identify a plant-derived compound, Concanavalin A (Con A), which differentially kills p53-null cells. Further, we find that p53 family member, p73, plays a critical role that is unmasked in the absence of p53. Con A treatment leads to induction of p73 and several others that are important mediators of apoptosis and act downstream, such as p21, Bax, Foxo1a, and Bim. Inactivation of p73 reverses the expression of these proteins and apoptosis. Inhibition of Akt activation sensitizes otherwise resistant cells. These observations thus reveal a novel role for p73 in the regulation of Akt-Foxo1a-Bim signaling and apoptosis especially when p53 is absent.
几乎所有人类癌症都会出现“p53网络”的破坏。从治疗角度来看，设计出消除癌细胞（其功能性p53通常存在缺陷）并保护表达p53的正常细胞的策略非常重要。通过比较一对同基因细胞系的反应，我们鉴定出一种植物来源的化合物，伴刀豆球蛋白A（Con A），它能差异性地杀死p53缺失的细胞。此外，我们发现p53家族成员p73发挥着关键作用，而这一作用在p53缺失时才会显现出来。Con A处理会导致p73以及其他几个凋亡的重要介质的诱导，这些介质在下游发挥作用，如p21、Bax、Foxo1a和Bim。p73的失活会逆转这些蛋白质的表达和凋亡。抑制Akt激活会使原本耐药的细胞敏感化。因此，这些观察结果揭示了p73在Akt - Foxo1a - Bim信号传导和凋亡调节中的新作用，尤其是在p53缺失时。
