Muppani Naveen, Nyman Ulrika, Joseph Bertrand
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, 171 76 Stockholm, Sweden.
Oncotarget. 2011 Dec;2(12):1145-54. doi: 10.18632/oncotarget.391.
Caspase-2 is ubiquitously expressed and the most evolutionarily conserved mammalian caspase. It can be activated by a range of death stimuli prior to Bax activation and the occurrence of apoptotic mitochondrial dysfunctions. Caspase-2 has also been reported to exert tumour suppressor function in vivo. The full length TAp73alpha isoform is found up-regulated in various tumour types, and is reported in a cell-type specific manner to repress drug-induced apoptosis. Here, we report that TAp73alpha represses caspase-2 enzymatic activity and by this means reduce caspase-2 induced Bax activation, loss of mitochondrial transmembrane potential and resulting apoptosis. The inhibitory effect on caspase-2 requires the presence of the DNA binding domain and SAM domain region of TAp73alpha. In conclusion, the ability of TAp73alpha to act as an inhibitor of caspase-2-induced cell death together with its up-regulation in certain tumour types strengthen the potential oncogenic activities for this protein.
半胱天冬酶 -2在全身广泛表达，是哺乳动物中进化上最保守的半胱天冬酶。在 Bax 激活和凋亡性线粒体功能障碍发生之前，它可被一系列死亡刺激激活。据报道，半胱天冬酶 -2 在体内也发挥肿瘤抑制功能。全长TAp73α 亚型在多种肿瘤类型中上调，并且据报道以细胞类型特异性方式抑制药物诱导的细胞凋亡。在此，我们报告 TAp73α 抑制半胱天冬酶 -2 的酶活性，并以此减少半胱天冬酶 -2 诱导的 Bax 激活、线粒体跨膜电位丧失及由此导致的细胞凋亡。对半胱天冬酶 -2 的抑制作用需要 TAp73α 的 DNA 结合结构域和 SAM 结构域区域的存在。总之，TAp73α 作为半胱天冬酶 -2 诱导的细胞死亡抑制剂的能力及其在某些肿瘤类型中的上调，增强了该蛋白潜在的致癌活性。
