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Merlin/Nf2-Mediated Tumor Suppression: From Mechanism To Translation

Author
Cooper, Jonathan
Abstract
The FERM domain protein Merlin, encoded by the NF2 tumor suppressor gene, regulates cell proliferation in response to adhesion signaling. The growth inhibitory function of Merlin is induced by intercellular adhesions and inactivated by joint integrin/receptor tyrosine kinase signaling. Merlin contributes to the formation of cell junctions in polarized tissues, activates anti-mitogenic signaling at tight-junctions, and inhibits oncogenic gene expression. Thus, inactivation of Merlin causes uncontrolled mitogenic signaling and tumorigenesis. The underlying molecular mechanisms driving Merlin’s tumor suppressive functions have remained largely elusive since its discovery over two decades ago. We show that Merlin’s predominant tumor suppressive functions are attributable to its inhibition of the CRL4DCAF1 E3 ubiquitin ligase in the nucleus. These findings are supported using in vitro and in vivo binding assays, multiple lines of genetic evidence, in vitro mouse models, and freshly explanted NF2 patient samples. We subsequently show that Merlin’s nuclear translocation and inhibition of CRL4DCAF1 suppresses inhibition of the Hippo tumor suppressor pathway kinases Lats1 and 2. Merlin’s inhibition of CRL4DCAF1 therefore promotes inhibition of the YAP and TAZ transcriptional coactivators and abrogates oncogenic signaling. I further develop a conditional Dcaf1 allele to assess the in vivo role of CRL4DCAF1 in Merlin-deficient mouse models. A rapid non-germline genetically engineered mouse model using fetal liver progenitor cells shows that DCAF1 is necessary for Merlin-deficient tumorigenesis. However, Dcaf1 deletion in the adult liver exacerbates hepatomegaly and tumorigenesis, which likely stems from the expansion of a bipotential hepatobiliary niche. I also set out to develop a rapid malignant pleural mesothelioma (MPM) mouse model using virally delivered constructs to simultaneously recombine conditional alleles and inhibit or somatically mutate cooperating tumor suppressors. Finally, I show that CRL4DCAF1 inhibition using the NEDD8 Activating Enzyme inhibitor MLN4924 reduces oncogenic signaling in Merlin-deficient MPM. Combining MLN4924 with traditional chemotherapy or mechanism-based therapy significantly delays the growth of Merlin-deficient MPM, a cancer that is highly refractory to standard chemotherapeutics. These latter findings support the use of MLN4924 in combination with mTOR/PI3K inhibitors for the treatment of Merlin-deficient tumors.
Date Issued
2016Subject
Cancer; DCAF1; Merlin; Mesothelioma; NF2; Ubiquitin Ligase
Degree Discipline
Cell & Developmental Biology
Degree Level
Doctor of Philosophy
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Type
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International