GFAP-Cre-Mediated Transgenic Activation of Bmi1 Results in Pituitary Tumors

Bmi1 is a member of the polycomb repressive complex 1 and plays different roles during embryonic development, depending on the developmental context. Bmi1 over expression is observed in many types of cancer, including tumors of astroglial and neural origin. Although genetic depletion of Bmi1 has been described to result in tumor inhibitory effects partly through INK4A/Arf mediated senescence and apoptosis and also through INK4A/Arf independent effects, it has not been proven that Bmi1 can be causally involved in the formation of these tumors. To see whether this is the case, we developed two conditional Bmi1 transgenic models that were crossed with GFAP-Cre mice to activate transgenic expression in neural and glial lineages. We show here that these mice generate intermediate and anterior lobe pituitary tumors that are positive for ACTH and beta-endorphin. Combined transgenic expression of Bmi1 together with conditional loss of Rb resulted in pituitary tumors but was insufficient to induce medulloblastoma therefore indicating that the oncogenic function of Bmi1 depends on regulation of p16INK4A/Rb rather than on regulation of p19ARF/p53. Human pituitary adenomas show Bmi1 overexpression in over 50% of the cases, which indicates that Bmi1 could be causally involved in formation of these tumors similarly as in our mouse model.Bmi1是多梳抑制复合体1（polycomb repressive complex 1）的组成成员，在胚胎发育过程中，其功能随发育背景的差异而发生变化。多种肿瘤中均检测到Bmi1过表达，包括星形胶质细胞起源及神经起源的肿瘤。尽管已有研究证实，Bmi1的基因敲除可通过INK4A/Arf介导的细胞衰老与凋亡通路，以及不依赖INK4A/Arf的通路发挥部分抑瘤效应，但目前尚未有证据表明Bmi1可直接因果性参与此类肿瘤的发生。为验证这一假说，本研究构建了两种条件性Bmi1转基因模型，并与胶质纤维酸性蛋白-Cre（GFAP-Cre）小鼠交配，以实现Bmi1在神经与胶质细胞谱系中的特异性激活表达。本研究结果显示，此类小鼠可产生促肾上腺皮质激素（ACTH）与β-内啡肽（beta-endorphin）阳性的垂体中间叶及前叶肿瘤。将Bmi1的转基因过表达与视网膜母细胞瘤蛋白（Rb）条件性敲除相结合，可诱导垂体肿瘤的发生，但无法诱发髓母细胞瘤，这提示Bmi1的致癌功能依赖于对p16INK4A/Rb通路的调控，而非p19ARF/p53通路。临床样本分析显示，超过50%的人垂体腺瘤样本中存在Bmi1过表达，这表明Bmi1可能如同本小鼠模型中所观察到的一样，因果性参与此类肿瘤的形成。