Germline and somatic cancer-associated mutations in the ATP-binding motifs of PTEN influence its subcellular localization and tumor suppressive function.
Germline and somatic cancer-associated mutations in the ATP-binding motifs of PTEN influence its subcellular localization and tumor suppressive function.
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DOI：
10.1093/hmg/ddp220
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发表时间：
2009-08-01
影响因子：
3.5
通讯作者：
Eng C
中科院分区：
文献类型：
--
作者：
Lobo GP;Waite KA;Planchon SM;Romigh T;Nassif NT;Eng C
在考登综合征（CS）和多发性散发性恶性肿瘤中分别发现了生殖系和体细胞PTEN突变。PTEN的功能似乎受到亚细胞区室化的调节，并且错误定位可能影响功能。我们已经表明，细胞ATP水平影响核PTEN水平。在这里，我们研究了与癌症相关突变相关的PTEN的ATP结合能力和功能后果。对CS患者和散发性结直肠癌进行PTEN突变分析，并进行比较氨基酸分析，以确定ATP结合基序的突变。通过ATP-琼脂糖结合测定评估野生型（WT）或突变型PTEN结合ATP的能力。亚细胞分级分离，蛋白质印迹，共聚焦显微镜和生长测定用于确定相对核质定位和功能。体细胞结直肠癌源性PTEN错义突变与核错误定位相关。这些突变改变了细胞增殖、凋亡和锚定依赖性生长。检查PTEN的氨基酸序列发现，这些突变存在于以前未描述的ATP结合基序中（c.60-73; c.122-136）。与WT PTEN相反，位于ATP结合基序内的癌症相关的体细胞和种系来源的PTEN错义突变导致不能有效结合ATP的突变体PTEN。我们还发现，生殖系ATP结合基序突变的CS患者有核PTEN错误定位。在4名具有功能性生殖系ATP结合结构域突变的无关患者中，所有3名女性患者均患有乳腺癌。PTEN的ATP结合结构域内的生殖系和体细胞突变通过导致改变的信号传导和生长的PTEN核错误定位在可遗传和散发性癌发生中起重要的致病作用。ATP的操纵可能代表了具有此类PTEN改变的肿瘤的新型疗法。
Germline and somatic PTEN mutations are found in Cowden syndrome (CS) and multiple sporadic malignancies, respectively. PTEN function appears to be modulated by subcellular compartmentalization, and mislocalization may affect function. We have shown that cellular ATP levels affect nuclear PTEN levels. Here, we examined the ATP-binding capabilities of PTEN and functional consequences, relevant to cancer-associated mutations. PTEN mutation analysis of CS patients and sporadic colorectal carcinomas and comparative aminoacid analysis were utilized to identify mutations in ATP-binding motifs. The ability of wild-type (WT) or mutant PTEN to bind ATP was assessed by ATP–agarose-binding assays. Subcellular fractionation, western blotting, confocal microscopy and growth assays were used to determine relative nuclear-cytoplasmic localization and function. Somatic colorectal carcinoma-derived PTEN missense mutations were associated with nuclear mislocalization. These mutations altered cellular proliferation, apoptosis and anchorage-dependent growth. Examination of PTEN's amino acid sequence revealed these mutations resided in previously undescribed ATP-binding motifs (c.60–73; c.122–136). In contrast to WT PTEN, both cancer-associated somatic and germline-derived PTEN missense mutations, which lie within the ATP-binding motifs, result in mutant PTEN that does not bind ATP efficiently. We also show that CS patients with germline ATP-binding motif-mutations had nuclear PTEN mislocalization. Of four unrelated patients with functional germline ATP-binding domain mutations, all three female patients had breast cancers. Germline and somatic mutations within PTEN's ATP-binding domain play important pathogenic roles in both heritable and sporadic carcinogenesis by PTEN nuclear mislocalization resulting in altered signaling and growth. Manipulation of ATP may represent novel therapies in tumors with such PTEN alterations.
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DOI：
10.1083/jcb.200506074
发表时间：
2005-10-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kose S;Furuta M;Koike M;Yoneda Y;Imamoto N
通讯作者：
Imamoto N
影响因子：
6.4
作者：
Whiteman, DC;Zhou, XP;Eng, C
通讯作者：
Eng, C
DOI：
10.1016/j.bbamcr.2006.07.015
发表时间：
2006-10-01
影响因子：
5.1
作者：
Wolfman, Janice C.;Planchon, Sarah M.;Wolfman, Alan
通讯作者：
Wolfman, Alan
影响因子：
3.5
作者：
Choi, Joung Woo;Lee, Sang Bae;Ahn, Jee-Yin
通讯作者：
Ahn, Jee-Yin
影响因子：
10.3
作者：
Mutter, GL;Lin, MC;Eng, C
通讯作者：
Eng, C