文章：

癌症中仅LIM结构域蛋白质类

LIM-domain-only proteins in cancer

原文发布日期：2013-01-10

DOI: 10.1038/nrc3418

类型: Review Article

开放获取: 否

要点：

1. All members of the human LIM-domain-only (LMO) family of proteins, LMO1–4, are implicated in the onset or the progression of cancers. In particular, LMO1 and LMO2 are linked to the onset of T cell leukaemia; overexpression of LMO4 is a marker of poor prognosis in breast cancer; and LMO1 and LMO3 are associated with neuroblastoma.
2. The overexpression of LMO2 in T cells is caused by chromosomal translocations (in which T cell receptor genes are inserted upstream of LMO2), chromosomal deletions, insertional mutagenesis during gene therapy trials for SCID-X1, and the upregulation of promoters though transcription factors such as FLI1, ERG and LMO2 itself.
3. LMO2-induced T cell leukaemias have a long latency period. The overexpression of LMO2 results in the upregulation of haematopoietic stem cell genes and the downregulation of T cell differentiation genes, which causes developing thymocytes to stall at the DN3 stage and to undergo self-renewal. The self-renewing cells can accumulate additional mutations (such as activating mutations of NOTCH1) that trigger overt leukaemia.
4. LMO2 seems to function primarily through forming transcription factor complexes with TAL1 or LYL1, GATA proteins, LDB1, and E12 or E47 to regulate gene expression. Other LMO proteins may function in the same way, but apart from LMO1 (which can take the place of LMO2 in haematopoietic transcriptional complexes) their protein partners are less well characterized.
5. LMO4 seems to regulate progression through the cell cycle in breast cancer cell lines, and can act at several different stages of the cell cycle, probably either by affecting transcriptional programmes of proteins that directly control cell cycle progression, or through interaction with such proteins.
6. The overexpression of LMO proteins has been identified in many different types of cancers. In some cases this overexpression can have a protective effect, in other cases the LMO proteins actively promote cancer, but in many other cases a causative or protective role has yet to be determined. In cancers in which LMO proteins are oncogenic, such as LMO2-induced T cell leukaemias, inhibitors of the LMO protein may be of therapeutic value.

要点翻译：

1. 人类LIM结构域仅蛋白（LMO）家族所有成员LMO1-4均与癌症的发生或进展相关。其中，LMO1和LMO2与T细胞白血病的发病相关；LMO4过表达是乳腺癌预后不良的标志；LMO1和LMO3则与神经母细胞瘤相关。
2. LMO2在T细胞中的过表达由多种机制引发：染色体易位（T细胞受体基因插入LMO2上游）、染色体缺失、SCID-X1基因治疗试验中的插入突变，以及通过FLI1、ERG和LMO2自身等转录因子对启动子的上调作用。
3. LMO2诱导的T细胞白血病具有较长潜伏期。LMO2过表达会导致造血干细胞基因上调及T细胞分化基因下调，使得发育中的胸腺细胞停滞在DN3阶段并发生自我更新。这些自我更新的细胞会累积额外突变（如NOTCH1激活突变），最终引发显性白血病。
4. LMO2主要通过与TAL1或LYL1、GATA蛋白、LDB1以及E12或E47形成转录因子复合物来调控基因表达。其他LMO蛋白可能具有类似功能，但除LMO1（可在造血转录复合物中替代LMO2）外，其蛋白相互作用网络的表征尚不完善。
5. 在乳腺癌细胞系中，LMO4可调控细胞周期进程，其作用可能通过影响直接调控细胞周期的蛋白转录程序，或与这类蛋白相互作用来实现，并可在细胞周期多个阶段发挥作用。
6. LMO蛋白的过表达已在多种癌症类型中被确认。某些情况下这种过表达具有保护效应，另一些情况下LMO蛋白会主动促进癌症发展，但在更多情形中其致病或保护作用尚未明确。对于LMO蛋白具有致癌性的癌症（如LMO2诱导的T细胞白血病），LMO蛋白抑制剂可能具有治疗价值。

英文摘要：

LIM-domain proteins are a large family of proteins that are emerging as key molecules in a wide variety of human cancers. In particular, all members of the human LIM-domain-only (LMO) proteins, LMO1–4, which are required for many developmental processes, are implicated in the onset or the progression of several cancers, including T cell leukaemia, breast cancer and neuroblastoma. These small proteins contain two protein-interacting LIM domains but little additional sequence, and they seem to function by nucleating the formation of new transcriptional complexes and/or by disrupting existing transcriptional complexes to modulate gene expression programmes. Through these activities, the LMO proteins have important cellular roles in processes that are relevant to cancer such as self-renewal, cell cycle regulation and metastasis. These functions highlight the therapeutic potential of targeting these proteins in cancer.

摘要翻译： 

LIM结构域蛋白是一个庞大的蛋白家族，正逐渐成为多种人类癌症中的关键分子。特别是人类LIM结构域唯一（LMO）蛋白家族的全部成员——LMO1至LMO4，它们对许多发育过程至关重要，却被证实与包括T细胞白血病、乳腺癌和神经母细胞瘤在内的多种癌症的发生和进展有关。这些小型蛋白仅含两个介导蛋白相互作用的LIM结构域，几乎无额外序列，其作用机制似乎是通过启动新的转录复合物形成和/或破坏现有转录复合物，从而调控基因表达程序。凭借这些活性，LMO蛋白在自我更新、细胞周期调控和转移等与癌症相关的进程中发挥重要细胞功能，突显了将这些蛋白作为癌症治疗靶点的潜力。

原文链接：

LIM-domain-only proteins in cancer