Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland
Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland
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DOI：
10.1128/mcb.25.7.2660-2672.2005
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发表时间：
2005-04-01
影响因子：
5.3
通讯作者：
Helin, K
中科院分区：
文献类型：
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作者：
Denchi, EL;Attwooll, C;Helin, K
视网膜母细胞瘤基因RB1是人类癌症中最常见的突变基因之一。 Rb杂合小鼠发生垂体肿瘤，发病率为100％，并且需要E2F转录因子。为了评估失调的E2F活性是否足以诱导垂体肿瘤，我们在垂体的中间叶中产生了表达诱导型E2F3蛋白的转基因小鼠。我们发现，E2F活性的短期放松管制，类似于最早的RB损失阶段，能够诱导异常静止的黑素营养物的异常增殖。但是，尽管长期暴露于失调的E2F活性导致中间叶的增生，但并未导致肿瘤形成。实际上，黑素营养物对持续的E2F刺激不敏感，并进入不可逆的衰老状态。因此，尽管E2F活性放松导致过度增殖，但它不足以模仿RB丧失，维持黑素营养的增殖并最终诱导垂体肿瘤。同样，我们发现组织培养中的原代细胞对持续的E2F3激活不敏感，并以PRB，P16（INK4A） - 和P19（ARF）依赖性方式以PRB-，P16（INK4A） - 和P19（ARF）依赖性方式进行过早衰老。因此，我们得出的结论是，由于衰老反应的参与，放松管制的E2F活性不足以完全模仿RB的损失。
The retinoblastoma gene, RB1, is one of the most frequently mutated genes in human cancer. Rb heterozygous mice develop pituitary tumors with 100% incidence, and the E2F transcription factors are required for this. To assess whether deregulated E2F activity is sufficient to induce pituitary tumors, we generated transgenic mice expressing an inducible E2F3 protein in the intermediate lobe of the pituitary gland. We found that short-term deregulation of E2F activity, similar to the earliest stages of Rb loss, is able to induce abnormal proliferation of otherwise quiescent melanotrophs. However, while long-term exposure to deregulated E2F activity results in hyperplasia of the intermediate lobe, it did not lead to tumor formation. In fact, melanotrophs become insensitive to sustained E2F stimulation and enter an irreversible senescence-like state. Thus, although deregulated E2F activity results in hyperproliferation, it is not sufficient to mimic loss of Rb, sustain proliferation of melanotrophs, and ultimately induce pituitary tumors. Similarly, we found that primary cells in tissue culture become insensitive to sustained E2F3 activation and undergo premature senescence in a pRB-, p16(Ink4a)-, and p19(Arf)-dependent manner. Thus, we conclude that deregulated E2F activity is not sufficient to fully mimic loss of Rb due to the engagement of a senescence response.