Loss of the Drosophila cell polarity regulator Scribbled promotes epithelial tissue overgrowth and cooperation with oncogenic Ras-Raf through impaired Hippo pathway signaling.
Loss of the Drosophila cell polarity regulator Scribbled promotes epithelial tissue overgrowth and cooperation with oncogenic Ras-Raf through impaired Hippo pathway signaling.
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DOI：
10.1186/1471-213x-11-57
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发表时间：
2011-09-29
影响因子：
--
通讯作者：
Brumby AM
中科院分区：
文献类型：
--
作者：
Doggett K;Grusche FA;Richardson HE;Brumby AM
上皮性肿瘤与细胞极性改变和细胞过度增殖有关，但这些肿瘤特性如何相互关联仍然知之甚少。通过调节这两种特性来研究作为肿瘤肿瘤抑制因子的果蝇基因具有阐明这一关系的重大潜力。在果蝇中，我们发现细胞极性调节因子scribble （Scrib）和肿瘤抑制因子的缺失会导致眼睛和翅膀成像盘上皮组织中的Hippo通路信号通路受损。scrib突变组织的过度生长，而不是细胞极性的丧失，依赖于有缺陷的Hippo信号，可以通过敲低TEAD/TEF家族转录因子扇贝或转录辅激活因子Yorkie在眼盘中，或降低Yorkie在翼盘中的水平来挽救。此外，Scrib的缺失使组织对致癌Ras-Raf信号传导的转化敏感，而yorky -扇贝活性是促进这种协同肿瘤过度生长所必需的。scrib突变眼盘克隆中Hippo信号的抑制不依赖于JNK活性，但可以通过降低aPKC激酶活性来显着挽救，并且即使JNK信号被阻断，异位aPKC活性也足以损害眼盘中的Hippo信号。相比之下，疣突变体的过度生长不需要aPKC活性。此外，降低内源性aPKC水平或增加Scrib或致死巨型幼虫水平并不会促进Hippo信号的增加，这表明aPKC活性通常不是Hippo通路活性的限速因子。显位实验表明，scrib突变体中的Hippo通路抑制至少部分发生在Hippo通路调控的扩展臂和脂肪臂的下游或平行发生。Scrib的缺失促进Yorkie/扇贝依赖的上皮组织过度生长，这对于通过致癌Ras-Raf信号驱动协同肿瘤过度生长也很重要。由于Scrib的细胞极性功能及其抑制癌基因介导转化的能力，以及Hippo通路的组织生长控制功能，在哺乳动物中是保守的，因此在人类癌症中是否也存在这种情况现在值得研究。
Epithelial neoplasias are associated with alterations in cell polarity and excessive cell proliferation, yet how these neoplastic properties are related to one another is still poorly understood. The study of Drosophila genes that function as neoplastic tumor suppressors by regulating both of these properties has significant potential to clarify this relationship. Here we show in Drosophila that loss of Scribbled (Scrib), a cell polarity regulator and neoplastic tumor suppressor, results in impaired Hippo pathway signaling in the epithelial tissues of both the eye and wing imaginal disc. scrib mutant tissue overgrowth, but not the loss of cell polarity, is dependent upon defective Hippo signaling and can be rescued by knockdown of either the TEAD/TEF family transcription factor Scalloped or the transcriptional coactivator Yorkie in the eye disc, or reducing levels of Yorkie in the wing disc. Furthermore, loss of Scrib sensitizes tissue to transformation by oncogenic Ras-Raf signaling, and Yorkie-Scalloped activity is required to promote this cooperative tumor overgrowth. The inhibition of Hippo signaling in scrib mutant eye disc clones is not dependent upon JNK activity, but can be significantly rescued by reducing aPKC kinase activity, and ectopic aPKC activity is sufficient to impair Hippo signaling in the eye disc, even when JNK signaling is blocked. In contrast, warts mutant overgrowth does not require aPKC activity. Moreover, reducing endogenous levels of aPKC or increasing Scrib or Lethal giant larvae levels does not promote increased Hippo signaling, suggesting that aPKC activity is not normally rate limiting for Hippo pathway activity. Epistasis experiments suggest that Hippo pathway inhibition in scrib mutants occurs, at least in part, downstream or in parallel to both the Expanded and Fat arms of Hippo pathway regulation. Loss of Scrib promotes Yorkie/Scalloped-dependent epithelial tissue overgrowth, and this is also important for driving cooperative tumor overgrowth with oncogenic Ras-Raf signaling. Whether this is also the case in human cancers now warrants investigation since the cell polarity function of Scrib and its capacity to restrain oncogene-mediated transformation, as well as the tissue growth control function of the Hippo pathway, are conserved in mammals.