Positional cloning of the pulmonary adenoma resistance 2 (Par2) locus of the mouse

BALB/cByJ小鼠的肺腺瘤抗性2（Par 2）基因座位于染色体18的0.5cM内，相对于C57 BL/6 J、A/J和C3 H/HeJ小鼠中的那些，其负责降低乳腺癌诱导的肺肿瘤的平均多样性。因此，除了携带C57 BL/6 J Par 2等位基因外，BALB/B6-Par 2同源株与BALB/cByJ遗传上相同，其肿瘤发生率是BALB/cByJ的7倍。为了获得鉴定Par 2候选基因的线索，我们分析了BALB/cByJ惠BALB. B6-Par 2嵌合动物中的肺肿瘤发生。在16个嵌合体中由乌拉坦诱导的100个肿瘤中，82个起源于BALB.B6-Par 2细胞，表明Par 2表型是细胞自主的。此外，BALB. B6-Par 2-和BALB/cByJ-衍生肿瘤的平均大小相似，这意味着表型主要在癌发生的起始阶段而不是在促进阶段表达。鉴于这些结果，我们调查了一个全面的小鼠基因组数据库，并在2.3 Mb范围内对Par 2进行了物理定位。 ...更多信息 p片段含有三个已知基因Poli、Mbd 2和Dcc。其中，Poli似乎是最合理的Par 2候选者，因为它编码一种非常容易出错的DNA聚合酶，在体外优先掺入与模板T相反的G或T，这让人想起由于密码子61内A到G或T的点突变而导致的Kras 2激活，大多数由密码子61引发的肺肿瘤都是由Kras 2激活引起的。事实上，我们对BALB/cByJ、C57 BL/6 J、A/J和C3 H/HeJ肺的Poli cDNA测序显示，编码区存在21个BALB/cByJ特异性单核苷酸多态性，伴有7个氨基酸取代和选择性剪接频率升高，而Mbd 2或Dcc均未发现与肿瘤易感性相关的多态性。值得注意的是，我们获得的证据表明，与C57 BL/6 J等位基因相比，BALB/cByJ Par 2等位基因可以选择性地降低kras 2突变肿瘤的频率。因此，波利是一个有趣的Par 2候选人显然值得进一步评估。少

The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops 7 times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analyzed lung tumorigenesis in BALB/cByJ ⇔ BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2- and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mb … More p segment containing three known genes, Poli, Mbd2 and Dcc. Among those, the Poli seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation due to an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Poli cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/HeJ lungs revealed 21BALB/cByJ-specific single nucleotide polymorphisms in the coding region accompanied by 7 amino acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation. Less