Abstract
BackgroundEpithelial 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.ResultsHere 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.ConclusionsLoss 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.
Highlights
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
Results scrib mutant eye disc cells exhibit impaired Hippo pathway signaling, and this does not require Jun N-terminal kinase (JNK) signaling We have previously reported that scrib mutant clones of tissue in the eye disc exhibit ectopic CycE expression and excessive cell proliferation, this is restrained through JNK-dependent apoptosis [39]
The ectopic cell proliferation in scrib mutant clones expressing bskDN is similar to mutants in the Hippo pathway, and to determine if the Hippo pathway is impaired by the loss of scrib, we examined known targets of Hippo-mediated repression in scrib mutant eye disc clones
Summary
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. Loss of Hippo pathway components leads to reduced phosphorylation of Yki and its translocation to the nucleus where it binds to its DNA binding partner, Scalloped (Sd), and promotes expression of proteins involved in cell proliferation (Cyclin E; CycE), cell growth (Myc) and cell survival (Drosophila Inhibitor of Apoptosis 1; DIAP1) [4,5,6,7,8,9,10,11]. It is the dual role of the Hippo pathway in regulating both cell proliferation and survival functions that makes its loss such a potent driver of tissue overgrowth. Increasing evidence links Hippo pathway deregulation to tumorigenesis [reviewed in [21]]
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