生物谷報(bào)道：通過抑制Hdm2/Mdm2 restore腫瘤細(xì)胞中的p53，是當(dāng)前腫瘤治療中的熱點(diǎn),。但是,，此方法是否可以激活正常細(xì)胞中的p53，從而影響到療效,，是科研人員的關(guān)注所在,。最近，來自美國(guó)加州大學(xué)圣地牙哥分校的科學(xué)家發(fā)現(xiàn),，在mdm2缺失的老鼠中,，正常細(xì)胞的p53表達(dá)被活化。這一結(jié)果發(fā)表在最新一期的《Cancer Cell》上,。
研究人員在實(shí)驗(yàn)中使用了一種內(nèi)源p53表達(dá)可調(diào)控的老鼠模型,，該老鼠模型可在野生型和突變型之間快速而可逆地轉(zhuǎn)變p53的水平（Homozygous p53KI/KI and heterozygous p53 KI/- and mdm2-/-;p53KI/- mice）,。結(jié)果發(fā)現(xiàn),，在mdm2缺失的老鼠中，被檢測(cè)的組織均活化表達(dá)p53,，并引起致死性的病理現(xiàn)象,，類似于急性的輻射引起的病理過程。在抗凋亡的組織中,，p53自發(fā)活化,，并抑制細(xì)胞增殖。并且p53的活化并未發(fā)現(xiàn)伴有翻譯后修飾,。
這一研究結(jié)果表明：通過敲除mdm2同樣可以在正常組織中活化p53,，因此,，在腫瘤組織中restore p53的腫瘤療法具有風(fēng)險(xiǎn)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.
原文出處：
Cancer Cell December, 2006: 10 (6)
Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo
Ingo Ringshausen, Clodagh C. O'Shea, Andrew J. Finch, Lamorna Brown Swigart, and Gerard I. Evan
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相關(guān)基因：
MDM2
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
Mdm2
Official Symbol: Mdm2 and Name: transformed mouse 3T3 cell double minute 2 [Mus musculus]
Other Aliases: 1700007J15Rik, AA415488, Mdm-2
Chromosome: 10; Location: 10 66.0 cM
GeneID: 17246
TP53
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
作者簡(jiǎn)介：
Gerard Evan, PhD
Molecular basis of carcinogenesis: regulation of cell proliferation and cell death (apoptosis)
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, I., Evan, G., and Blasco, M. A. (2006). Genetic analysis of myc and telomerase interactions in vivo. Mol Cell Biol 26, 6130-6138.
Christophorou, M.A., Ringshausen I., Finch A.J., Brown Swigart L. and Evan, G.I. (2006). The pathological response to DNA damage does not contribute to p53-mediated tumor suppression. Nature 443, 214-217.
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.
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.
