癌症的发生往往是由于肿瘤细胞获得了脱离细胞死亡宿命的能力，在人类的癌症病例中，细胞死亡现象的缺失大部分是源于一个关键基因——P53的突变。P53是细胞凋亡的一个重要调节分子，同时也是一个明星抑癌基因。因此，在P53缺失的情形下，如何使肿瘤细胞以其它的方式发生凋亡是十分重要的方向。P73是P53家族的另一成员，可以行使与P53相似的生物功能，然而不同于P53的高突变率，P73在癌症中鲜有突变发生。这使得P73成为控制癌细胞凋亡的关键。针对这一问题，作者展开了相关研究，研究结果发表在最近一期的《Oncogene》杂志上。
作者之前已经鉴定出ADORA2B（即编码腺嘌呤受体A2B的基因）是P53基因下游的效应基因，该基因的活化能够导致细胞在外界腺嘌呤浓度达到一定程度的情况下发生细胞凋亡。因此，作者希望了解是否该基因也会受到P73的调节。
首先，作者以Saos-2细胞系作为研究对象，构建了P73的诱导过表达系统，他们发现在P73有效表达的情况下，ADORA2B的表达水平也会显著上升。这一结果说明P73与P53类似，都能激活下游基因ADORA2B的表达。由于ADORA2B本身带有P53结合位点，因此，作者希望了解是否该结合位点也能够与P73相互结合。作者通过荧光素酶报告基因的检测手段（即在细胞系中共同转染P73质粒与带有P53结合位点序列的质粒），结果显示，P73能够与ADORA2B基因内部的P53结合位点相互结合，进一步肯定了P73的生理功能。
下一步，作者希望了解P73激活ADORA2B基因的表达从而产生A2B受体对细胞本身的影响。在此前的实验设计基础上，作者后续加入了腺嘌呤的类似物（NECA）刺激。结果显示，在P73表达量较低时，无论是否有NECA的刺激，细胞的死亡率均较低，而当P73诱导表达量升高时，本身即会引起大量细胞的死亡，在加入NECA的刺激后，这一比例变得更高。这一结果说明P73激活下游ADORA2B基因的表达能够进一步促进细胞的凋亡发生。
进一步，作者通过生化实验确定了细胞的凋亡事件的发生依赖于caspase 激酶的活性。并通过一系列抑制剂/抑制分子的实验证明该凋亡主要是内源性（即由线粒体引发，细胞色素C介导发生的）而非外源性。
最终，作者证明了在接受放射性治疗或药物治疗后的肿瘤细胞中P73能够增强A2B的信号，从而促使细胞凋亡的发生。
【相关会议推荐】
2015（第二届）自噬转化医学与疾病研讨会 12.17-18 上海
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Effects of upregulation of Id3 in human lung adenocarcinoma cells on proliferation, apoptosis, mobility and tumorigenicity
J S Long, P M Schoonen, D Graczyk, J O'Prey and K M Ryan
Tumour cells often acquire the ability to escape cell death, a key event leading to the development of cancer. In almost half of all human cancers, the capability to induce cell death is reduced by the mutation and inactivation of p53, a tumour suppressor protein that is a central regulator of apoptosis. As a result, there is a crucial need to identify different cell death pathways that could be targeted in malignancies lacking p53. p73, the closely related p53 family member, can regulate many p53 target genes and therefore some of the same cellular responses as p53. Unlike p53, however, p73 is seldom mutated in cancer, making it an attractive, alternative death effector to target. We report here the ability of p73 to upregulate the expression of the A2B receptor, a recently characterized p53 target that effectively promotes cell death in response to extracellular adenosine-a metabolite that accumulates during various forms of cellular stress. importantly, we show that p73-dependent stimulation of A2B signalling markedly enhances apoptosis in cancer cells that are devoid of p53. This mode of death is caspase- and puma-dependent, and can be prevented by the overexpression of anti-apoptotic Bcl-XL. Moreover, treatment of p53-null cancer cells with the chemotherapeutic drug adriamycin (doxorubicin) induces A2B in a p73-dependent manner and, in combination with an A2B agonist, substantially enhances apoptotic death. We therefore propose an alternate and distinct p53-independent pathway to stimulate programmed cell death involving p73-mediated engagement of adenosine signalling.