Real-time in vivo imaging of p16Ink4a reveals cross talk with p53.
Real-time in vivo imaging of p16Ink4a reveals cross talk with p53.
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P16INK4A的实时体内成像揭示了与p53的交叉对话。
DOI：
10.1083/jcb.200904105
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发表时间：
2009-08-10
期刊：
影响因子：
--
通讯作者：
Hara E
中科院分区：
文献类型：
--
作者：
Yamakoshi K;Takahashi A;Hirota F;Nakayama R;Ishimaru N;Kubo Y;Mann DJ;Ohmura M;Hirao A;Saya H;Arase S;Hayashi Y;Nakao K;Matsumoto M;Ohtani N;Hara E
P16INK4a肿瘤抑制基因是致癌压力的感受器，在培养的原代细胞中被各种潜在的致癌刺激上调。然而，由于p16INK4a的表达也是由组织培养胁迫诱导的，所以调控p16INK4a表达的生理机制尚不清楚。为了消除组织培养施加的压力带来的任何潜在问题，我们使用生物发光成像技术对活体小鼠在不同生理条件下p16INK4a的表达进行了非侵入性和实时分析。在这项研究中，我们表明，致癌的侮辱，如ras的激活，在体内通过降低DNMT1(DNA甲基转移酶1)的水平作为DNA损伤反应而引起表观遗传下调p16INK4a的表达。这一途径在没有P53的情况下被加速，表明P53通常控制着p16INK4a的反应。这些结果揭示了p16INK4a在p53失活情况下的备用肿瘤抑制作用，扩大了我们对p16INK4a表达在体内如何调控的理解。
Expression of the p16Ink4a tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16Ink4a expression is also induced by tissue culture stress, physiological mechanisms regulating p16Ink4a expression remain unclear. To eliminate any potential problems arising from tissue culture–imposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of p16Ink4a expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16Ink4a expression through reduction of DNMT1 (DNA methyl transferase 1) levels as a DNA damage response in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16Ink4a response in check. These results unveil a backup tumor suppressor role for p16Ink4a in the event of p53 inactivation, expanding our understanding of how p16Ink4a expression is regulated in vivo.
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