LAPSER1/LZTS2: a pluripotent tumor suppressor linked to the inhibition of katanin-mediated microtubule severing
LAPSER1/LZTS2: a pluripotent tumor suppressor linked to the inhibition of katanin-mediated microtubule severing
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DOI：
10.1093/hmg/ddn153
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发表时间：
2008-08-15
影响因子：
3.5
通讯作者：
Maru, Yoshiro
中科院分区：
文献类型：
--
作者：
Sudo, Haruka;Maru, Yoshiro
人类染色体10q23-24区域是前列腺癌中最常发现的杂合性缺失区域之一。候选肿瘤抑制基因LAPSER1/LZTS2 （LAPSER1）位于10q24.3，据报道，它与邻近的PTEN位点一样频繁地被删除。我们之前报道过LAPSER1结合p80 katanin，这是katanin异源二聚体的一个亚基。在本报告中，我们发现LAPSER1 C末端结构域在体外抑制katanin介导的微管切断，我们通过追踪细胞中有核的新生、切断和运输的微管在中心体上检测到这种抑制作用。这种功能关联也得到细胞内定位的支持。LAPSER1的中心体定位与微管无关，并优先于母中心粒。在原代培养的神经元中，LAPSER1也与p80 katanin共定位。LAPSER1通过调节细胞分裂改变细胞增殖。作为肿瘤抑制活性的亚细胞机制，外源性LAPSER1表达通过取消微管运输来抑制中央纺锤体的形成，并且在轴生中发现了类似的抑制模式。Katanin敲低和Katanin显性阴性抑制剂具有相似的表型。前期LAPSER1抑制中心体γ -微管蛋白积累，导致有丝分裂进入延迟。此外，LAPSER1表达对katanin的间期抑制导致细胞运动的阻止，并伴有乙酰化微管的增加。LAPSER1敲低增加了细胞迁移，这被微管释放抑制剂九蛋白的表达所抑制。这些结果表明，中心体微管切断是细胞中一个新的肿瘤相关分子亚回路，其中LAPSER1是一个调节因子。
Human chromosome region 10q23-24 is one of the most frequently found regions that show loss of heterozygosity in prostate cancers. A candidate tumor suppressor LAPSER1/LZTS2 (LAPSER1) is located in 10q24.3 that has been reported to be deleted as frequently as the neighboring PTEN locus. We previously reported that LAPSER1 binds p80 katanin, a subunit of the katanin heterodimer. In this report, we show that the LAPSER1 C terminal domain inhibits katanin-mediated microtubule severing in vitro and we detected this inhibition at centrosomes by tracing the nucleated de novo, severed, and transported microtubules in cells. This functional association is also supported by the intracellular localization. Centrosomal localization of LAPSER1 was independent of microtubules and was preferential to mother centrioles. In primary cultured neurons, LAPSER1 also colocalizes with p80 katanin. LAPSER1 alters cell proliferation by regulating cytokinesis. As subcellular mechanisms that underlie the tumor suppressive activity, exogenous LAPSER1 expression inhibited central spindle formation by abrogating microtubule transportation and a similar mode of inhibition was found in axogenesis. Katanin knockdown and dominant negative inhibitor of katanin provided similar phenotypes. Prophase LAPSER1 inhibited centrosomal gamma-tubulin accumulation, which resulted in retardation of mitotic entry. Furthermore, interphase inhibition of katanin by LAPSER1 expression resulted in prevention of cell motility that was accompanied by the increased acetylated microtubules. LAPSER1 knockdown increased cell migration that was inhibited by the expression of ninein, a microtubule release inhibitor. These results indicate that microtubule severing at centrosomes is a novel tumor-associated molecular subcircuit in cells, in which LAPSER1 is a regulator.