Haploinsufficiency at the Nkx3.1 locus:: A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation
Haploinsufficiency at the Nkx3.1 locus:: A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation
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DOI：
10.1016/s1535-6108(03)00047-3
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发表时间：
2003-03-01
期刊：
影响因子：
50.3
通讯作者：
Milbrandt, J
中科院分区：
文献类型：
--
作者：
Magee, JA;Abdulkadir, SA;Milbrandt, J
肿瘤发生需要多个遗传病变的连续积累。在前列腺中，肿瘤的发生通常与Nkx3.1基因座的杂合性丢失有关。在小鼠中，即使一个Nkx3.1等位基因的丢失也会导致前列腺上皮增生和最终的前列腺上皮内瘤形成（PIN）。在这里，我们表明，Nkx3.1等位基因的损失延长再生管腔细胞的增殖阶段，导致上皮增生。微阵列分析确定了Nkx3.1靶基因，其中许多显示出精致的剂量敏感性。Nkx3.1等位基因的数量决定了给定靶基因随机激活或失活的相对概率。因此，单个Nkx3.1等位基因的丢失可能通过增加受影响细胞亚群内选择Nkx3.1调节途径完全失活的可能性而导致增生和PIN。
Tumorigenesis requires sequential accumulation of multiple genetic lesions. In the prostate, tumor initiation is often linked to loss of heterozygosity at the Nkx3.1 locus. In mice, loss of even one Nkx3.1 allele causes prostatic epithelial hyperplasia and eventual prostatic intraepithelial neoplasia (PIN) formation. Here we demonstrate that Nkx3.1 allelic loss extends the proliferative stage of regenerating luminal cells, leading to epithelial hyperplasia. Microarray analysis identified Nkx3.1 target genes, many of which show exquisite dosage sensitivity. The number of Nkx3.1 alleles determines the relative probabilities of stochastic activation or inactivation of a given target gene. Thus, loss of a single Nkx3.1 allele likely results in hyperplasia and PIN by increasing the probability of completely inactivating select Nkx3.1-regulated pathways within a subset of affected cells.