Department of Pathology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143, USA.
Genes Dev. 2011 Aug 15;25(16):1746-57. doi: 10.1101/gad.16722111.
MdmX, also known as Mdm4, is a critical negative regulator of p53, and its overexpression serves to block p53 tumor suppressor function in many cancers. Consequently, inhibiting MdmX has emerged as an attractive approach to restoring p53 function in those cancers that retain functional p53. However, the consequences of acute systemic MdmX inhibition in normal adult tissues remain unknown. To determine directly the effects of systemic MdmX inhibition in normal tissues and in tumors, we crossed mdmX(-/-) mice into the p53ER(TAM) knockin background. In place of wild-type p53, p53ER(TAM) knockin mice express a variant of p53, p53ER(TAM), that is completely dependent on 4-hydroxy-tamoxifen for its activity. MdmX inhibition was then modeled by restoring p53 function in these MdmX-deficient mice. We show that MdmX is continuously required to buffer p53 activity in adult normal tissues and their stem cells. Importantly, the effects of transient p53 restoration in the absence of MdmX are nonlethal and reversible, unlike transient p53 restoration in the absence of Mdm2, which is ineluctably lethal. We also show that the therapeutic impact of restoring p53 in a tumor model is enhanced in the absence of MdmX, affording a significant extension of life span over p53 restoration in the presence of MdmX. Hence, systemic inhibition of MdmX is both a feasible therapeutic strategy for restoring p53 function in tumors that retain wild-type p53 and likely to be significantly safer than inhibition of Mdm2.
X 女士，也被称为 Mdm4，是 p53 的关键负调控因子，其过表达可在许多癌症中阻断 p53 肿瘤抑制功能。因此，抑制 MdmX 已成为恢复那些保留功能性 p53 的癌症中 p53 功能的一种有吸引力的方法。然而，急性全身 MdmX 抑制在正常成年组织中的后果仍然未知。为了直接确定全身 MdmX 抑制在正常组织和肿瘤中的影响，我们将 mdmX(-/-) 小鼠与 p53ER(TAM) 基因敲入背景杂交。在 p53ER(TAM) 基因敲入小鼠中，用 p53ER(TAM) 变体取代野生型 p53，p53ER(TAM) 是完全依赖于 4-羟基他莫昔芬发挥其活性的。然后通过在这些 MdmX 缺陷型小鼠中恢复 p53 功能来模拟 MdmX 抑制。我们表明，MdmX 连续需要缓冲成年正常组织及其干细胞中的 p53 活性。重要的是，在没有 MdmX 的情况下短暂恢复 p53 的影响是非致命和可逆的，与在没有 Mdm2 的情况下短暂恢复 p53 不同，后者是不可避免的致命的。我们还表明，在没有 MdmX 的情况下恢复 p53 在肿瘤模型中的治疗效果增强，与在有 MdmX 的情况下恢复 p53 相比，显著延长了寿命。因此，全身抑制 MdmX 不仅是恢复保留野生型 p53 的肿瘤中 p53 功能的可行治疗策略，而且可能比抑制 Mdm2 安全得多。
