RINT-1 serves as a tumor suppressor and maintains Golgi dynamics and centrosome integrity for cell survival
RINT-1 serves as a tumor suppressor and maintains Golgi dynamics and centrosome integrity for cell survival
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DOI：
10.1128/mcb.02396-06
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发表时间：
2007-07-01
影响因子：
5.3
通讯作者：
Lee, Wen-Hwa
中科院分区：
文献类型：
--
作者：
Lin, Xiaoqin;Liu, Chang-Ching;Lee, Wen-Hwa
高尔基体和中心体在有丝分裂中的正确分配对细胞的正常分裂至关重要。虽然这两个细胞质细胞器可能在细胞分裂过程中协调，但这种协调的支持证据仍然很大程度上缺乏。在这里，我们表明，RAD 50相互作用的蛋白质，RINT-1，位于高尔基体和中心体除了内质网。为了研究Rint-1的生物学作用，我们发现Rint-1的纯合缺失导致胚胎第5天（E5）至E6的早期胚胎死亡和胚泡体外生长失败。约81%的Rint-1杂合子在平均24个月的寿命内死于单倍缺陷的多发性肿瘤形成。为了确定RINT-1的细胞功能，我们发现通过RNA干扰的RINT-1缺失导致高尔基体的中心粒周围定位和分散的丧失以及间期期间的中心体扩增。有丝分裂进入后，RINT-1缺陷的细胞表现出多种异常，包括异常的高尔基体动力学在早期有丝分裂和有缺陷的重组在末期，增加形成多个纺锤体极，和频繁的染色体错误分离。有丝分裂细胞经常经历细胞死亡，部分原因是压倒性的细胞缺陷。总之，这些研究结果表明，RINT-1作为一种新的肿瘤抑制因子，对维持高尔基体和中心体的动态完整性至关重要，这是细胞分裂过程中它们适当协调的先决条件。
Faithful mitotic partitioning of the Golgi apparatus and the centrosome is critical for proper cell division. Although these two cytoplasmic organelles are probably coordinated during cell division, supporting evidence of this coordination is still largely lacking. Here, we show that the RAD50-interacting protein, RINT-1, is localized at the Golgi apparatus and the centrosome in addition to the endoplasmic reticulum. To examine the biological roles of RINT-1, we found that the homozygous deletion of Rint-1 caused early embryonic lethality at embryonic day 5 (E5) to E6 and the failure of blastocyst outgrowth ex vivo. About 81% of the Rint-1 heterozygotes succumbed to multiple tumor formation with haploinsutficiency during their average life span of 24 months. To pinpoint the cellular function of RINT-1, we found that RINT-1 depletion by RNA interference led to the loss of the pericentriolar positioning and dispersal of the Golgi apparatus and concurrent centrosome amplification during the interphase. Upon mitotic entry, RINT-1-deficient cells exhibited multiple abnormalities, including aberrant Golgi dynamics during early mitosis and defective reassembly at telophase, increased formation of multiple spindle poles, and frequent chromosome missegregation. Mitotic cells often underwent cell death in part due to the overwhelming cellular defects. Taken together, these findings suggest that RINT-1 serves as a novel tumor suppressor essential for maintaining the dynamic integrity of the Golgi apparatus and the centrosome, a prerequisite to their proper coordination during cell division.