Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice.
Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice.
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DOI：
10.7150/ijbs.9241
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发表时间：
2014
影响因子：
9.2
通讯作者：
Tsuzuki T
中科院分区：
文献类型：
--
作者：
Isoda T;Nakatsu Y;Yamauchi K;Piao J;Yao T;Honda H;Nakabeppu Y;Tsuzuki T
MUTYH是一种DNA糖基化酶，其切除与8-氧代鸟嘌呤配对的腺嘌呤以防止哺乳动物中的诱变。MUTYH的双等位基因种系突变已在易患隐性形式的家族性腺瘤性息肉病（MAP：MUTYH相关息肉病）的患者中发现。我们以前报道过Mutyh缺陷小鼠对自发性和氧化应激诱导的肠腺瘤/癌表现出高度的易感性。在这里，我们进行了突变分析的肿瘤相关基因，包括Apc，Ctnnb 1，Kras和Trp 53在Mutyh缺陷小鼠的肠道肿瘤。在62个肿瘤中，我们发现18个肿瘤的Apc中有25个突变，36个肿瘤的Ctnnb 1中有36个突变。总的来说，62个肿瘤中有54个（87.1%）在Apc或Ctnnb 1中有突变;没有肿瘤在两个基因中同时显示突变。与MAP相似，61个突变中的60个（98.3%）被鉴定为G：C到T：A颠换，其中85%发生在AGAA或TGAA序列。免疫组织化学分析显示β-catenin在肿瘤细胞核中积聚。Kras和Trp 53在肿瘤中均未发现突变。这些结果表明，Wnt信号通路的不受控制的激活与氧化应激诱导的Mutyh缺陷小鼠的肠道肿瘤发生有因果关系。
MUTYH is a DNA glycosylase that excises adenine paired with 8-oxoguanine to prevent mutagenesis in mammals. Biallelic germline mutations of MUTYH have been found in patients predisposed to a recessive form of familial adenomatous polyposis (MAP: MUTYH-associated polyposis). We previously reported that Mutyh-deficient mice showed a high susceptibility to spontaneous and oxidative stress-induced intestinal adenoma/carcinoma. Here, we performed mutation analysis of the tumor-associated genes including Apc, Ctnnb1, Kras and Trp53 in the intestinal tumors of Mutyh-deficient mice. In the 62 tumors, we identified 25 mutations in Apc of 18 tumors and 36 mutations in Ctnnb1 of 36 tumors. Altogether, 54 out of the 62 tumors (87.1%) had a mutation in either Apc or Ctnnb1; no tumor displayed mutations simultaneously in the both genes. Similar to MAP, 60 out of 61 mutations (98.3%) were identified as G:C to T:A transversions of which 85% occurred at either AGAA or TGAA sequences. Immunohistochemical analyses revealed the accumulation of β-catenin in the nuclei of tumors. No mutation was found in either Kras or Trp53 in the tumors. These results indicate that the uncontrolled activation of Wnt signaling pathway is causatively associated with oxidative stress-induced intestinal tumorigenesis in the Mutyh-deficient mice.
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影响因子：
64.5
作者：
GRODEN, J;THLIVERIS, A;WHITE, R
通讯作者：
WHITE, R
影响因子：
56.9
作者：
NISHISHO, I;NAKAMURA, Y;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
14.9
作者：
Ohtsubo, T;Nishioka, K;Nakabeppu, Y
通讯作者：
Nakabeppu, Y
DOI：
10.1073/pnas.87.19.7555
发表时间：
1990-10-01
影响因子：
11.1
作者：
RODRIGUES, NR;ROWAN, A;LANE, DP
通讯作者：
LANE, DP
影响因子：
3.3
作者：
Nishioka, K;Ohtsubo, T;Nakabeppu, Y
通讯作者：
Nakabeppu, Y