Tubulin tyrosine ligase like 12 links to prostate cancer through tubulin posttranslational modification and chromosome ploidy
Tubulin tyrosine ligase like 12 links to prostate cancer through tubulin posttranslational modification and chromosome ploidy
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DOI：
10.1002/ijc.25261
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发表时间：
2010-12-01
影响因子：
6.4
通讯作者：
Wasylyk, Bohdan
中科院分区：
文献类型：
--
作者：
Wasylyk, Christine;Zambrano, Alberto;Wasylyk, Bohdan
前列腺癌是一种常见的死亡原因，一个重要的目标是建立致病基因的途径和功能。我们分离了在宏观解剖的前列腺癌样品中差异表达的RNA。这项研究集中在一个确定的基因，TTLL12，这是预测修改微管蛋白，肿瘤治疗的既定目标。TTLL12是最近发现的催化微管蛋白翻译后修饰的14个成员蛋白质家族中特征最差的成员。我们发现，人TTLL12在良性前列腺的增殖层中表达。在癌症进展至转移期间表达增加。它在许多转移性前列腺癌细胞系中高度表达。它部分共定位于波形蛋白中间丝和含有微管蛋白的细胞结构，包括中间体，中心体，细胞间桥和有丝分裂纺锤体。TTLL12的下调影响微管蛋白的几种翻译后修饰（脱酪氨酸和随后的脱谷氨酰化和多聚谷氨酰化）。过表达改变染色体倍性。这些结果提高了TTLL 12可能通过影响细胞骨架、微管蛋白修饰和染色体数目稳定性而促进肿瘤发生的可能性。这项研究为开发针对微管的更具选择性的药物迈出了一步，微管是肿瘤治疗的一个成功靶点。
Prostate cancer is a common cause of death, and an important goal is to establish the pathways and functions of causative genes. We isolated RNAs that are differentially expressed in macrodissected prostate cancer samples. This study focused on 1 identified gene, TTLL12, which was predicted to modify tubulins, an established target for tumor therapy. TTLL12 is the most poorly characterized member of a recently discovered 14-member family of proteins that catalyze posttranslational modification of tubulins. We show that human TTLL12 is expressed in the proliferating layer of benign prostate. Expression increases during cancer progression to metastasis. It is highly expressed in many metastatic prostate cancer cell lines. It partially colocalizes with vimentin intermediate filaments and cellular structures containing tubulin, including midbodies, centrosomes, intercellular bridges and the mitotic spindle. Downregulation of TTLL12 affects several posttranslational modifications of tubulin (detyrosination and subsequent deglutamylation and polyglutamylation). Overexpression alters chromosomal ploidy. These results raise the possibility that TTLL12 could contribute to tumorigenesis through effects on the cytoskeleton, tubulin modification and chromosome number stability. This study contributes a step toward developing more selective agents targeting microtubules, an already successful target for tumor therapy.