High levels of Hdmx promote cell growth in a subset of uveal melanomas.
High levels of Hdmx promote cell growth in a subset of uveal melanomas.
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发表时间：
2012
影响因子：
5.3
通讯作者：
J. de Lange;A. Teunisse;M. V. Vries;K. Lodder;S. Lam;G. Luyten;F. Bernal;M. Jager;A. Jochemsen
中科院分区：
文献类型：
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作者：
J. de Lange;A. Teunisse;M. V. Vries;K. Lodder;S. Lam;G. Luyten;F. Bernal;M. Jager;A. Jochemsen
在癌症中，通过直接突变或通过上游调节因子或下游效应因子的解除调控，P53肿瘤抑制因子途径被失活。葡萄膜黑色素瘤中很少发生P53突变。在这里，我们研究了P53抑制剂Hdmx在葡萄膜黑色素瘤中的作用。我们发现Hdmx在葡萄膜黑色素瘤细胞系和新鲜冷冻的肿瘤样本中过表达。Hdmx的缺失导致细胞系依赖的生长抑制，明显与不同的Hdm2水平相关。令人惊讶的是，p53基因敲除几乎不能挽救Hdmx基因敲除后的细胞周期停滞和细胞凋亡诱导，而它却有效地阻止了强大的P53激活剂Nutlin-3诱导的生长抑制。此外，抑制Hdmx功能或表达的两个化合物SAH-P53-8和XI-011也以部分P53非依赖的方式产生生长抑制作用。这些发现表明，Hdmx具有一种新的促进生长的功能，它不依赖于它抑制P53的能力。我们提供的证据表明，p27蛋白的诱导在Hdmx基因敲除后观察到的P53非依赖性G1期停滞中起到了作用。总之，我们的研究确定了hdmx作为一种癌基因在葡萄膜黑色素瘤亚群中的重要性，并拓宽了它的功能范围，使其超越了p53的抑制。
The p53 tumor suppressor pathway is inactivated in cancer either via direct mutation or via deregulation of upstream regulators or downstream effectors. P53 mutations are rare in uveal melanoma. Here we investigated the role of the p53 inhibitor Hdmx in uveal melanoma. We found Hdmx over-expression in a subset of uveal melanoma cell lines and fresh-frozen tumor samples. Hdmx depletion resulted in cell-line dependent growth inhibition, apparently correlating with differential Hdm2 levels. Surprisingly, p53 knockdown hardly rescued cell cycle arrest and apoptosis induction upon Hdmx knockdown, whereas it effectively prevented growth suppression induced by the potent p53 activator Nutlin-3. In addition, two compounds inhibiting Hdmx function or expression, SAH-p53-8 and XI-011, also elicited a growth inhibitory effect in a partly p53-independent manner. These findings suggest a novel, growth-promoting function of Hdmx that does not rely on its ability to inhibit p53. We provide evidence for a contribution of p27 protein induction to the observed p53-independent G1 arrest in response to Hdmx knockdown. In conclusion, our study establishes the importance of Hdmx as an oncogene in a subset of uveal melanomas and widens the spectrum of its function beyond p53 inhibition.