Wei Chongjuan, Amos Christopher I, Stephens L Clifton, Campos Imelda, Deng Jian Min, Behringer Richard R, Rashid Asif, Frazier Marsha L
Department of Epidemiology, The University of Texas, MD Anderson Cancer Center, Houston, 77030, USA.
Cancer Res. 2005 Dec 15;65(24):11297-303. doi: 10.1158/0008-5472.CAN-05-0716.
Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1(+/-) and p53 null mice to generate Lkb1(+/-)/p53(+/-) and Lkb1(+/-)/p53(-/-) mice. Similar to the Lkb1(+/-) mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1(+/-)/p53(+/-) mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1(+/-)/p53(-/-) mice is approximately 2 months earlier than Lkb1(+/-)/p53(+/-) and Lkb1(+/-) mice, whereas the latter two show a similar time to onset which is at approximately 6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis.
黑斑息肉综合征（PJS）是一种常染色体显性遗传病，其特征为胃肠道错构瘤性息肉和黏膜皮肤黑色素沉着。LKB1基因的种系突变会导致PJS。我们通过对胚胎干细胞进行基因靶向操作，培育出携带Lkb1外显子2至8缺失的小鼠。杂合子会发展出胃错构瘤，其组织学特征与患有PJS的人类患者相似。据报道，LKB1也是p53依赖的细胞凋亡的介导因子。为了探究p53和Lkb1改变对肿瘤发生的潜在联合效应，我们将Lkb1(+/-)小鼠与p53基因敲除小鼠进行了一系列杂交，培育出Lkb1(+/-)/p53(+/-)和Lkb1(+/-)/p53(-/-)小鼠。与Lkb1(+/-)小鼠相似，这两种基因型的小鼠也检测到了胃肠道错构瘤。与Lkb1或p53单基因敲除的小鼠相比，Lkb1(+/-)/p53(+/-)小鼠的寿命显著缩短，肿瘤发生率增加。Lkb1(+/-)/p53(-/-)小鼠息肉病发病时间比Lkb1(+/-)/p53(+/-)和Lkb1(+/-)小鼠早约2个月，而后两者的发病时间相似，约为6月龄。这些结果有力地表明，p53和Lkb1基因突变在肿瘤发生加速过程中相互协作。
