Fbw7 and Usp28 - enemies and allies.
Ontology highlight
ABSTRACT:
SUBMITTER: Taranets L
PROVIDER: S-EPMC4905318 | biostudies-other | 2015 Jul-Sep
REPOSITORIES: biostudies-other
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Project description:The enemy release hypothesis (ERH) attributes the success of some exotic plant species to reduced top-down effects of natural enemies in the non-native range relative to the native range. Many studies have tested this idea, but very few have considered the simultaneous effects of multiple kinds of enemies on more than one invasive species in both the native and non-native ranges. Here, we examined the effects of two important groups of natural enemies-insect herbivores and soil biota-on the performance of Tanacetum vulgare (native to Europe but invasive in the USA) and Solidago canadensis (native to the USA but invasive in Europe) in their native and non-native ranges, and in the presence and absence of competition.In the field, we replicated full-factorial experiments that crossed insecticide, T. vulgare-S. canadensis competition, and biogeographic range (Europe vs. USA) treatments. In greenhouses, we replicated full-factorial experiments that crossed soil sterilization, plant-soil feedback, and biogeographic range treatments. We evaluated the effects of experimental treatments on T. vulgare and S. canadensis biomass.The effects of natural enemies were idiosyncratic. In the non-native range and relative to populations in the native range, T. vulgare escaped the negative effects of insect herbivores but not soil biota, depending upon the presence of S. canadensis; and S. canadensis escaped the negative effects of soil biota but not insect herbivores, regardless of competition. Thus, biogeographic escape from natural enemies depended upon the enemies, the invader, and competition. Synthesis: By explicitly testing the ERH in terms of more than one kind of enemy, more than one invader, and more than one continent, this study enhances our nuanced perspective of how natural enemies can influence the performance of invasive species in their native and non-native ranges.
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Project description:The stability of several oncoproteins, including c-Myc, is regulated by ubiquitin-dependent degradation mediated by the SCF(Fbw7) ubiquitin ligase. This activity is antagonized by the deubiquitinase Usp28, which is highly expressed in murine and human intestinal cancers. Usp28 was previously shown to interact with its substrates via a "piggyback" interaction with Fbw7, which suggested that Fbw7 is required for Usp28 activity. Unexpectedly, we found that genetic deletion of Usp28 rescued the lethality of Fbw7-deficient primary fibroblasts. Moreover, Usp28 inactivation in the intestine (Usp28(?IEC)) ameliorated the hyperproliferation and the impaired goblet and Paneth cell differentiation observed in Fbw7(?IEC) mice. The aggressive intestinal tumor formation of APC(Min/+); Fbw7(?IEC) mice was restrained when Usp28 was inactivated concomitantly. In both fibroblasts and intestinal cells, Usp28 deficiency corrected the accumulation of SCF(Fbw7) substrate proteins, including NICD1, c-Jun, and c-Myc. These findings suggested that Usp28 function does not depend on the presence of Fbw7, but instead independently recognizes and deubiquitylates the same substrates as SCF(Fbw7). Fbw7 binds to a phosphorylated motif termed the phosphodegron and we found that Usp28 also interacted with this same motif, but only when it is unphosphorylated, offering a mechanistic explanation for identical substrate selection by Fbw7 and Usp28. Our results indicate an unusually direct antagonism between an E3 ligase and a deubiquitinase, Fbw7 and Usp28, in modulating intestinal homeostasis and cancer.
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Project description:Fbw7 and Cdh1 are substrate-recognition subunits of the SCF- and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCF(Fbw7) substrates, including cyclin E, but also have increased expression of various APC(Cdh1) substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APC(Cdh1) activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APC(Cdh1) substrates to levels comparable to those in wild-type (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APC(Cdh1) substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APC(Cdh1) substrates in Fbw7-deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCF(Fbw7) and APC(Cdh1) substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors.
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Project description:FBW7 tumor suppressor suppresses the growth and survival of tumor cells by promoting the degradation of several oncoproteins, and induces endothelial differentiation by modulating the NF1/RAS axis. A recent study in this issue of Cell Research showed that FBW7 further regulates endothelial functions via degrading transcription factor KLF2.
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