The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development
The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development
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DOI：
10.1073/pnas.0805003105
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发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Longmore, Gregory D.
中科院分区：
文献类型：
--
作者：
Sharp, Tyson V.;Al-Attar, Ahmad;Longmore, Gregory D.
染色体3p21.3的杂合性丢失（洛）和纯合性缺失在小细胞肺癌和非小细胞肺癌中均很常见，提示可能存在肿瘤抑制基因（TSGs）。虽然该区域内的遗传和表观遗传变化已被确定，这些变化的功能意义尚未探讨。目前还没有人肺肿瘤的蛋白质表达和遗传分析以及功能研究。在这里，我们表明，表达的3p21.3基因，LIMD 1，经常下调，在人类肺肿瘤。LIMD 1表达的缺失通过基因缺失、洛和转录的表观遗传沉默的组合发生，而没有编码区突变的证据。在实验上，LIMD 1是真正的TSG。Limd 1（-/-）小鼠易患化学诱导的肺腺癌，在致癌K-Ras（G12 D）杂合子小鼠中Limd 1的基因失活显著增加肿瘤的发生、发展和死亡率。因此，我们得出结论，LIMD 1是一个验证的染色体3p21.3肿瘤抑制基因参与人类肺癌的发展。LIMD 1是一种含有LIM结构域的衔接蛋白，定位于E-钙粘蛋白细胞-细胞粘附连接处，但也易位到细胞核，在那里它已被证明作为RB辅阻遏物发挥作用。因此，LIMD 1具有将细胞外部或环境线索与核反应进行通信的潜力。
Loss of heterozygosity (LOH) and homozygous deletions at chromosome 3p21.3 are common in both small and nonsmall cell lung cancers, indicating the likely presence of tumor suppressor genes (TSGs). Although genetic and epigenetic changes within this region have been identified, the functional significance of these changes has not been explored. Concurrent protein expression and genetic analyses of human lung tumors coupled with functional studies have not been done. Here, we show that expression of the 3p21.3 gene, LIMD1, is frequently down-regulated in human lung tumors. Loss of LIMD1 expression occurs through a combination of gene deletion, LOH, and epigenetic silencing of transcription without evidence for coding region mutations. Experimentally, LIMD1 is a bona fide TSG. Limd1(-/-) mice are predisposed to chemical-induced lung adenocarcinoma and genetic inactivation of Limd1 in mice heterozygous for oncogenic K-Ras(G12D) markedly increased tumor initiation, promotion, and mortality. Thus, we conclude that LIMD1 is a validated chromosome 3p21.3 tumor-suppressor gene involved in human lung cancer development. LIMD1 is a LIM domain containing adapter protein that localizes to E-cadherin cell-cell adhesive junctions, yet also translocates to the nucleus where it has been shown to function as an RB corepressor. As such, LIMD1 has the potential to communicate cell extrinsic or environmental cues with nuclear responses.