Cell：研究发现restore p53的肿瘤疗法具有风险性
生物谷报道：通过抑制Hdm2/Mdm2 restore肿瘤细胞中的p53，是当前肿瘤治疗中的热点。但是，此方法是否可以激活正常细胞中的p53，从而影响到疗效，是科研人员的关注所在。最近，来自美国加州大学圣地牙哥分校的科学家发现，在mdm2缺失的老鼠中，正常细胞的p53表达被活化。这一结果发表在最新一期的《Cancer Cell》上。 研究人员在实验中使用了一种内源p53表达可调控的老鼠模型，该老鼠模型可在野生型和突变型之间快速而可逆地转变p53的水平（Homozygous p53KI/KI and heterozygous p53 KI/- and mdm2-/-;p53KI/- mice）。结果发现，在mdm2缺失的老鼠中，被检测的组织均活化表达p53，并引起致死性的病理现象，类似于急性的辐射引起的病理过程。在抗凋亡的组织中，p53自发活化，并抑制细胞增殖。并且p53的活化并未发现伴有翻译后修饰。 这一研究结果表明：通过敲除mdm2同样可以在正常组织中活化p53，因此，在肿瘤组织中restore p53的肿瘤疗法具有风险性。 Figure 2. Restoration of p53 function is acutely lethal to adult mice in the absence of Mdm2 and ablates radiosensitive tissues mdm2−/−;p53KI/− mice were treated daily with Tamoxifen, and tissues from all organs were harvested from moribund mice at day 5 (prior to death). Control animals included mdm2−/−;p53KI/− mice treated with oil and mdm2+/+;p53KI/−, mdm2−/−;p53−/− mice treated daily with Tamoxifen. Tissue sections were stained with H&E. Restoration of p53 function effectively ablated bone marrow, thymus, and white pulp of the spleen and induced dramatic atrophy of both small and large intestines (A). In sharp contrast, classically radio-resistant tissues such as brain, lung, heart, liver, and kidney remained unaffected (B) and indistinguishable from those of control mice. 原文出处： Cancer Cell December, 2006: 10 (6) Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo 相关基因： Official Symbol: MDM2 and Name: Mdm2, transformed 3T3 cell double minute 2, p53 binding protein (mouse) [Homo sapiens] Other Aliases: HDMX, MGC71221, hdm2 Other Designations: mouse double minute 2 homolog; mouse double minute 2, human homolog of; p53-binding protein; p53-binding protein MDM2; ubiquitin-protein ligase E3 Mdm2 Chromosome: 12; Location: 12q14.3-q15 MIM: 164785 GeneID: 4193 Official Symbol: Mdm2 and Name: transformed mouse 3T3 cell double minute 2 [Mus musculus] Other Aliases: 1700007J15Rik, AA415488, Mdm-2 Chromosome: 10; Location: 10 GeneID: 17246 Official Symbol: Tp53 and Name: tumor protein p53 (Li-Fraumeni syndrome) [Homo sapiens] Other Aliases: LFS1, TRP53, p53 Other Designations: p53 tumor suppressor; tumor protein p53 Chromosome: 17; Location: 17p13.1 MIM: 191170 GeneID: 7157 作者简介： Gerard Evan, PhD Selected Publications | Complete Publications Our laboratory is interested in the molecular processes that underlie tumorigenesis, tumor progression and tumor maintenance. Cancers appear very different from the normal tissues from which they are presumably derived, and this has engendered the widely held contemporary view that cancers are the protracted end result of a bewildering complexity of molecular lesions that between them drive the formation of the equally complex neoplastic phenotype. However, appearances can be deceiving. We know that many oncogenes are highly pleiotropic "master" switches that modulate a wide variety of mechanistically diverse processes. Consequently, the apparent complexity of cancers may be instructed by a relatively simple, and hence therapeutically tractable, set of molecular lesions. Our overarching aim is to establish what such molecular lesions might be, what effects they have on specific cell types, alone and in combination, and how critical such lesions are not only to drive tumor formation but also to maintain an established tumor.Some years ago we noted an unexpected link between the processes that drive cell proliferation and those that promote programmed cell death (apoptosis). We showed that the ubiquitous Myc oncoprotein was a potent trigger of apoptosis in cells deprived of survival factors or subjected to any of a diverse range of insults including DNA damage, interferon and death receptor signaling, hypoxia and nutrient privation. On the basis of such observations, we proposed the now generally accepted notion that the coupling of cell proliferation with cell death represents an innate tumor suppressive mechanism that efficiently restrains the emergence of autonomous clones within the soma. Thus, no cancer can arise without concomitant suppression of cell death. This, in turn, raises some critical questions. First, how does cell death become suppressed during tumorigenesis? Second, besides deregulated cell proliferation and suppressed cell death, what else (if anything) is needed for a cancer to arise? Third, how important is suppression of cell death for the maintenance of established cancers? In particular, might reconstitution of cell death offer an effective and tumor-specific general therapeutic strategy for treating cancer? Much of the work in our laboratory addresses these key questions using a variety of novel experimental systems and technologies. In particular, we are developing a number of new types of reversibly switchable mouse transgenic, knock-in, knock-out and gene replacement models with which to explore when, where, how and why specific oncogenes and tumor suppressors exert their effects in the development of normal and neoplastic tissues. Selected Publications Dansen, T. B., Whitfield, J., Rostker, F., Brown-Swigart, L., and Evan, G. I. (2006). Specific requirement for Bax, not Bak, in MYC-induced apoptosis and tumor suppression in vivo. J Biol Chem 281, 10890-95. Lawlor, E. R., Soucek, L., Brown-Swigart, L., Shchors, K., Bialucha, C. U., and Evan, G. I. (2006). Reversible Kinetic Analysis of Myc Targets In vivo Provides Novel Insights into Myc-Mediated Tumorigenesis. Cancer Res 66. 4591-601. Jelluma, N., Yang, X., Stokoe, D., Evan, G., Dansen, T., and Haas-Kogan, D. 2006. Glucose withdrawal induces oxidative stress followed by apoptosis in glioblastoma cells but not in normal human astrocytes. Mol Cancer Res 4: 319-330. Finch, A. J., Prescott, J., Shchors, K., Hunt, A., Soucel, L., Dansen, T. D., Brown Swigart, L. and Evan, G. I. (2006). Bcl-xL gain of function and ARF loss of function cooperate oncogenically with Myc in vivo by distinct mechanisms. Cancer Cell 10: 113-120. Flores, Christophorou, M.A., Shchors, K., Shchors, E., Rostker, F., Lawlor, E. R., Brown Swigart, L. and Evan, G. I. (2006) The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1b. Genes & Dev. 18, 2527-2538. 相关报道： Cancer Research：中南大学肿瘤研究所等发表p53新发现 Nature：研究发现抑癌蛋白p53中抑制其活性的甲基化位点
Ingo Ringshausen, Clodagh C. O'Shea, Andrew J. Finch, Lamorna Brown Swigart, and Gerard I. Evan
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Molecular basis of carcinogenesis: regulation of cell proliferation and cell death (apoptosis)
Ringshausen, I, O'Shea, C., Finch, A. J., Brown Swigart, L. and Evan, G. I. (2006) Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell, in press.
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