Unregulated smooth-muscle myosin in human intestinal neoplasia
Unregulated smooth-muscle myosin in human intestinal neoplasia
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DOI：
10.1073/pnas.0801213105
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发表时间：
2008-04-08
影响因子：
11.1
通讯作者：
Aaltonen, Lauri A.
中科院分区：
文献类型：
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作者：
Alhopuro, Pia;Phichith, Denis;Aaltonen, Lauri A.
最近的一项研究描述了斑马鱼熔毁 (mlt) 表型背后的隐性 ATP 酶激活平滑肌肌球蛋白 (smmhc/myh11) 种系突变。 mlt 斑马鱼出现肠道异常，让人想起人类黑斑息肉病 (PJS) 和幼年息肉病 (JP)。为了研究 MYH11 在人类肠道肿瘤中的作用，我们在结直肠癌 (CRC)、PJS 和 JP 患者中搜索了 MYH11 突变。我们在 55% 表现出微卫星不稳定性的 CRC 以及一名 PJS 个体的种系中发现了体细胞蛋白延长移码突变。此外，在一个微卫星稳定结直肠癌中发现了两个体细胞错义突变。对这两种错义突变 R501L 和 K1044N 以及移码突变进行了功能评估。所有突变都会导致不受调节的分子表现出组成性运动活性，类似于 MLT 中的突变肌球蛋白。因此，MYH11 突变似乎也与人类肠道肿瘤有关。不受调节的 MYH11 可能会影响细胞能量平衡或扰乱肿瘤祖细胞中的细胞谱系决策。这些数据挑战了我们对 MYH11 作为肌肉收缩中的被动分化标记物的看法，并增加了我们对肠道肿瘤的理解。
A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia.