Herz Hans-Martin, Woodfield Sarah E, Chen Zhihong, Bolduc Clare, Bergmann Andreas
Department of Biochemistry and Molecular Biology, The Genes & Development Graduate Program, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2009;4(1):e4165. doi: 10.1371/journal.pone.0004165. Epub 2009 Jan 9.
Genetic studies in yeast have identified class E vps genes that form the ESCRT complexes required for protein sorting at the early endosome. In Drosophila, mutations of the ESCRT-II component vps25 cause endosomal defects leading to accumulation of Notch protein and increased Notch pathway activity. These endosomal and signaling defects are thought to account for several phenotypes. Depending on the developmental context, two different types of overgrowth can be detected. Tissue predominantly mutant for vps25 displays neoplastic tumor characteristics. In contrast, vps25 mutant clones in a wild-type background trigger hyperplastic overgrowth in a non-autonomous manner. In addition, vps25 mutant clones also promote apoptotic resistance in a non-autonomous manner.
Here, we genetically characterize the remaining ESCRT-II components vps22 and vps36. Like vps25, mutants of vps22 and vps36 display endosomal defects, accumulate Notch protein and--when the tissue is predominantly mutant--show neoplastic tumor characteristics. However, despite these common phenotypes, they have distinct non-autonomous phenotypes. While vps22 mutations cause strong non-autonomous overgrowth, they do not affect apoptotic resistance. In contrast, vps36 mutations increase apoptotic resistance, but have little effect on non-autonomous proliferation. Further characterization reveals that although all ESCRT-II mutants accumulate Notch protein, only vps22 and vps25 mutations trigger Notch activity.
CONCLUSIONS/SIGNIFICANCE: The ESCRT-II components vps22, vps25 and vps36 display common and distinct genetic properties. Our data redefine the role of Notch for hyperplastic and neoplastic overgrowth in these mutants. While Notch is required for hyperplastic growth, it appears to be dispensable for neoplastic transformation.
酵母中的遗传学研究已鉴定出E类vps基因，这些基因形成早期内体蛋白分选所需的ESCRT复合物。在果蝇中，ESCRT-II组分vps25的突变会导致内体缺陷，从而导致Notch蛋白积累并增加Notch信号通路活性。这些内体和信号缺陷被认为是多种表型的原因。根据发育背景，可以检测到两种不同类型的过度生长。主要为vps25突变的组织表现出肿瘤特征。相比之下，野生型背景中的vps25突变克隆以非自主方式引发增生性过度生长。此外，vps25突变克隆也以非自主方式促进细胞凋亡抗性。
在这里，我们对其余的ESCRT-II组分vps22和vps36进行了遗传学特征分析。与vps25一样，vps22和vps36的突变体表现出内体缺陷，积累Notch蛋白，并且当组织主要为突变体时，表现出肿瘤特征。然而，尽管有这些共同的表型，但它们具有不同的非自主表型。虽然vps22突变会导致强烈的非自主过度生长，但它们不会影响细胞凋亡抗性。相比之下，vps36突变会增加细胞凋亡抗性，但对非自主增殖影响很小。进一步的特征分析表明，尽管所有ESCRT-II突变体都积累Notch蛋白，但只有vps22和vps25突变会触发Notch活性。
结论/意义：ESCRT-II组分vps22、vps25和vps36表现出共同和独特的遗传特性。我们的数据重新定义了Notch在这些突变体中增生性和肿瘤性过度生长中的作用。虽然Notch是增生性生长所必需的，但它似乎对于肿瘤转化是可有可无的。
