生物谷报道:许多癌症发生与抑癌基因缺陷有关，美国麻省理工学院的研究者首次发现，抑癌基因的在激活可缩小肿瘤，甚至可以使肿瘤消失。该研究提供的证据显示，抑癌基p53将成为非常有前景的人类肿瘤药物的作用靶点。
作为领衔共同作者之一的，来自美国麻省理工学院癌症研究中心和哈佛医科学校的David Kirsch说：“如果我们能够找到药物能够有效的修复p53功能，打开被阻断的通路，那将成为有效的癌症治疗方法。”该研究发表在自然杂志1月24日的电子版上。完成该实验研究的有癌症研究中心主任Tyler Jacks、生物学教授David H. Koch和哈佛Hughes医学研究所的研究者。
很久以来一直认为p53在许多肿瘤的发生过程中扮演关键角色，50％以上人类癌症中有p53的突变。尽管研究者已经发现一些化合物能够修复P53的功能，但直到现在，仍不能确定这些活性是否能够真正逆转原发肿瘤的生长。美国麻省理工学院的最新研究显示，再活化的p53可明显的缩小小鼠肿瘤，在某些小鼠甚至可以完全消除肿瘤。该论文的第一作者，癌症研究中心的博士后，意大利人Andrea Ventura说：“持续的肿瘤抑制基因的表达是肿瘤存活的必需条件，我们研究为其提供了重要的遗传学依据。”
在正常的细胞内，p53控制细胞周期。换而言之，当功能正常时，它激活DNA修复机制并能防止损伤的DNA分裂。当DNA损伤不能修复，p53将诱导细胞凋亡或程序性细胞死亡。当p53因突变或缺失而关闭，细胞分裂将不受控制，即使DNA损伤，因此细胞将更有可能癌变。在这项研究中，研究者应用p53关闭的工程小鼠，同时这项小鼠有一个遗传学开关，研究者应用它可在肿瘤发生后将p53打开。一旦肿瘤细胞内的p53激活，大多数肿瘤细胞缩小40％到100％。研究者观察两种不同类型癌症，淋巴瘤和肉瘤。在淋巴瘤或白细胞来源的癌症组，p53在活化1或2天，癌细胞均发生凋亡。相反，肉瘤（来源于结缔组织）不发生凋亡，而是进入一种衰老的状态或不生长，这些肿瘤细胞慢慢缩小，最后逐渐被清除。研究者不确定这两种癌症是否发生了不同的方式的影响，但是他们已经开始尽力去寻找在p53在活化后其他激活基因。
该研究也显示，开启p53对正常细胞无损害。此前，研究者一直担心p53将杀死正常细胞，因为正常细胞的p53从不表达。Ventura说：“这意味着，可以设计修复p53的药物，而不必担心其毒副作用。”包含能够修复突变的p53蛋白功能的小分子用于开启肿瘤细胞p53以及向肿瘤细胞内引入新的p53的基因治疗技术将成为可能的治疗方法。现在在研的一类潜在的药物，如nutlins，能够阻断鼠双微基因2，该酶可维持p53低水平。
在后续的研究中，美国麻省理工学院的研究者将在他们的小鼠模型中观察其他类型的癌症，如上皮癌。他们计划观察，是否相同的方法，不是p53，也能够抑制肿瘤。
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).
原文出处:
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
相关基因:
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
作者简介:
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
