生物谷報道:許多癌癥發(fā)生與抑癌基因缺陷有關(guān),，美國麻省理工學院的研究者首次發(fā)現(xiàn)，抑癌基因的在激活可縮小腫瘤,，甚至可以使腫瘤消失,。該研究提供的證據(jù)顯示，抑癌基p53將成為非常有前景的人類腫瘤藥物的作用靶點,。
    作為領(lǐng)銜共同作者之一的,，來自美國麻省理工學院癌癥研究中心和哈佛醫(yī)科學校的David Kirsch說：“如果我們能夠找到藥物能夠有效的修復p53功能，打開被阻斷的通路,，那將成為有效的癌癥治療方法,。”該研究發(fā)表在自然雜志1月24日的電子版上。完成該實驗研究的有癌癥研究中心主任Tyler Jacks,、生物學教授David H. Koch和哈佛Hughes醫(yī)學研究所的研究者,。

很久以來一直認為p53在許多腫瘤的發(fā)生過程中扮演關(guān)鍵角色，50％以上人類癌癥中有p53的突變,。盡管研究者已經(jīng)發(fā)現(xiàn)一些化合物能夠修復P53的功能,，但直到現(xiàn)在，仍不能確定這些活性是否能夠真正逆轉(zhuǎn)原發(fā)腫瘤的生長,。美國麻省理工學院的最新研究顯示,，再活化的p53可明顯的縮小小鼠腫瘤，在某些小鼠甚至可以完全消除腫瘤,。該論文的第一作者,，癌癥研究中心的博士后，意大利人Andrea Ventura說：“持續(xù)的腫瘤抑制基因的表達是腫瘤存活的必需條件,，我們研究為其提供了重要的遺傳學依據(jù),。”
    在正常的細胞內(nèi)，p53控制細胞周期,。換而言之,，當功能正常時,，它激活DNA修復機制并能防止損傷的DNA分裂。當DNA損傷不能修復,，p53將誘導細胞凋亡或程序性細胞死亡,。當p53因突變或缺失而關(guān)閉，細胞分裂將不受控制,，即使DNA損傷,，因此細胞將更有可能癌變。在這項研究中,，研究者應(yīng)用p53關(guān)閉的工程小鼠,，同時這項小鼠有一個遺傳學開關(guān)，研究者應(yīng)用它可在腫瘤發(fā)生后將p53打開,。一旦腫瘤細胞內(nèi)的p53激活,，大多數(shù)腫瘤細胞縮小40％到100％。研究者觀察兩種不同類型癌癥,，淋巴瘤和肉瘤,。在淋巴瘤或白細胞來源的癌癥組，p53在活化1或2天,，癌細胞均發(fā)生凋亡,。相反，肉瘤（來源于結(jié)締組織）不發(fā)生凋亡,，而是進入一種衰老的狀態(tài)或不生長,，這些腫瘤細胞慢慢縮小，最后逐漸被清除,。研究者不確定這兩種癌癥是否發(fā)生了不同的方式的影響,，但是他們已經(jīng)開始盡力去尋找在p53在活化后其他激活基因。
    該研究也顯示,，開啟p53對正常細胞無損害,。此前，研究者一直擔心p53將殺死正常細胞,，因為正常細胞的p53從不表達。Ventura說：“這意味著,，可以設(shè)計修復p53的藥物,，而不必擔心其毒副作用。”包含能夠修復突變的p53蛋白功能的小分子用于開啟腫瘤細胞p53以及向腫瘤細胞內(nèi)引入新的p53的基因治療技術(shù)將成為可能的治療方法?，F(xiàn)在在研的一類潛在的藥物,，如nutlins，能夠阻斷鼠雙微基因2,，該酶可維持p53低水平,。
    在后續(xù)的研究中,，美國麻省理工學院的研究者將在他們的小鼠模型中觀察其他類型的癌癥，如上皮癌,。他們計劃觀察,，是否相同的方法，不是p53,，也能夠抑制腫瘤,。

FIGURE 2. p53 restoration leads to tumour regression in vivo.

a, Flow chart of the strategy used to determine tumour response. i.p., intraperitoneal. b–d, MRI images (top) and tumour volumes (bottom) of p53-LSL;Cre-ERT2 (b, c) and p53-LSL (d, e) mice in response to tamoxifen (arrows). The tumours (asterisks) were an abdominal lymphoma (b), two thymic lymphomas (t. lymphoma; c and d, white asterisks) and two sarcomas (c and e, red asterisks). The volumes were calculated from the available MRI sequences (n  =  2 to 6) for each time point, and are shown as mean + 1 s.d. f, Summary of maximal responses to tamoxifen of tumours from Cre-ERT2-positive (grey bars) and Cre-ERT2-negative (blue bars) mice. Asterisks indicate tumours from Cre-ERT2-positive mice with limited or no response (see also Supplementary Fig. S3).

原文出處:

Restoration of p53 function leads to tumour regression in vivo
Andrea Ventura, David G. Kirsch, Margaret E. McLaughlin, David A. Tuveson, Jan Grimm, Laura Lintault, Jamie Newman, Elizabeth E. Reczek, Ralph Weissleder and Tyler Jacks

doi:10.1038/nature05541

First paragraph | Full Text | PDF (775K) | Supplementary information

See also: News and Views by Sharpless & DePinho

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Wen Xue, Lars Zender, Cornelius Miething, Ross A. Dickins, Eva Hernando, Valery Krizhanovsky, Carlos Cordon-Cardo and Scott W. Lowe

doi:10.1038/nature05529

First paragraph | Full Text | PDF (990K) | Supplementary information

See also: News and Views by Sharpless & DePinho

相關(guān)基因:

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

作者簡介:

Tyler Jacks

Professor Howard Hughes Medical Institute Center for Cancer Research Massachusetts Institute of Technology
Research interests:

Genetic Events Contributing to Oncogenesis

My laboratory is interested in the genetic events that contribute to the development of cancer. The focus of the work is a series of mouse strains in which we have engineered mutations in genes known to be involved in human cancer.

Mouse models for human familial cancer syndromes: It has recently been shown that a number of human familial cancer syndromes ( in which affected individuals have a greatly increased risk of developing particular types of cancer) are caused by the inheritance of a mutant allele of a tumor suppressor gene. These genes are thought to normally negatively regulate cell growth and they contribute to carcinogenesis when mutated or lost. Thus, individuals who carry only one functional copy of a given tumor suppressor gene are predisposed to cancer because all of their cells are just one mutational event from lacking an important negative growth regulator. Examples of diseases (and genes) in this class are: familial retinoblastoma (RB), neurofibromatosis type I and type II (NF1, NF2), Li-Fraumeni syndrome (p53), and familial adenomatous polyposis (APC).

Over the past several years, we have used gene targeting in mouse embryonic stem cells to create novel mouse strains with mutations in the murine homologues of several tumor suppressor genes. To date, we have constructed strains with germline mutations in Rb, Nf1, Nf2, p53 and Apc. Animals that are heterozygous for these mutations mimic (at least genetically) humans with one of the familial cancer syndromes mentioned above. The effects of some of these mutations in the mouse are consistent the human disease phenotypes, and in other cases there are clear species-specific differences. For example, humans who are heterozygous for an RB mutation have a 90% likelihood of developing retinoblastoma (a tumor of the eye), while we have not observed a single case of this tumor in several hundred Rb heterozygous mice examined. Instead, the Rb mutant mice are highly predisposed to pituitary tumors, with a penetrance of nearly 100%. In contrast, heterozygous mutation of the p53 gene causes predisposition to a similar spectrum of tumors in humans and mice. Through interbreeding of the different tumor suppressor gene-deficient strains, we are also examining possible synergistic effects of the multiple mutations.

The role of tumor suppressor genes in development: In addition to studying the effects of heterozygosity for tumor suppressor gene mutations, we are interested in the developmental consequences of homozygosity for these mutations. An understanding of the homozygous phenotype may provide clues to the function of these genes in normal cells and indicate why their loss contributes to carcinogenesis. We have carried out the heterozygous crosses for all of the mutant strains described above and determined that Rb, Nf1, Nf2, and Apc are all required for normal mouse development. Deficiency for Rb function leads to defective erythropoiesis and neurogenesis and the eventual death of the embryo by days 14-15 of gestation. The survival of Rb homozygotes to mid-gestation was somewhat surprising, and we have gone on to mutate the Rb-related genes, p107 and p130, to investigate possible functional redundancy in this gene family. Nf1 and Apc homozygotes show defects in cardiac and neural development, respectively, while Nf2-deficient embryos fail prior to day 8 of gestation.

Use of cell lines derived from mutant mice to probe the function of tumor suppressor genes in vitro: In addition to studying the effects of mutations of different tumor suppressor genes in the context of the whole animal, we are using cells isolated from the mutant mice to begin to investigate the function of these genes in vitro. Primary embryo fibroblast cultures have been isolated from embryos that are homozygous for a mutation in Rb, Nf1, or p53 as well as from the appropriate heterozygous and wild type controls. Since these cells are isogenic except for the mutations in the tumor suppressor genes, any phenotypic differences observed between the homozygotes and controls can be attributed to the known mutation and should reflect a function of the tumor suppressor gene. These experiments have focused to date on the role of Rb in transcriptional control during the cell cycle and on the importance of p53 in the normal cellular responses to DNA damage and other adverse conditions. For example, we have shown that p53-deficient fibroblasts fail to arrest their growth during the G1 phase of the cell cycle in response to gamma irradiation. Also, immature thymocytes which lack p53 function do not undergo programmed cell death (apoptosis) following irradiation. In addition, we have shown that p53 function is also required for the execution of the apoptotic pathway in response to the expression of the adenovirus E1A oncogene. This observation suggests that another mechanism by which p53 can effect tumor suppression is through the elimination of cells that have already acquired oncogenic mutations. Finally, p53-dependent apoptosis is also an important determinant of the sensitivity of tumor cells to various anti-cancer agents. We are currently examining the functional domains of p53 required for these various biological effects as well as constructing a mouse strain carrying a mutation in the p21 gene, which encodes a cyclin-cdk inhibitor thought to be an important downstream effector of p53 function.

Oncogene mutations. We have complemented our research on tumor suppressor gene mutations with one oncogene project. We have created two germline mutations of the K-ras gene. The first of these is a loss-of-function mutation in the gene. Embryos lacking K-ras function die with associated defects in liver function and generalized developmental delay; thus, of the three mammalian Ras proteins (K-, N-, and H-Ras), K-Ras is the only one essential for development. We have also used a modified "hit-and-run" gene targeting protocol to create an allele of K-ras that can be activated to an oncogenic state upon somatic mutation. The tumorigenic consequences of this mutation are currently under study.

Scott W. Lowe, Ph.D.

Scott W. Lowe, Ph.D
Professor/Deputy Director, Cancer Center
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
Research Field: Cancer Biology