Inhibition of FOXO3 Tumor Suppressor Function by βTrCP1 through Ubiquitin-Mediated Degradation in a Tumor Mouse Model

The ubiquitin-proteasome system is the primary proteolysis machine for controlling protein stability of the majority of regulatory proteins including those that are critical for cancer development. The forkhead box transcription factor FOXO3 plays a key role in regulating tumor suppression; however, the control of FOXO3 protein stability remains to be established. It is crucial to elucidate the molecular mechanisms underlying the ubiquitin-mediated degradation of FOXO3 tumor suppressor.Here we show that betaTrCP1 oncogenic ubiquitin E3-ligase interacts with FOXO3 and induces its ubiquitin-dependent degradation in an IkappaB kinase-beta phosphorylation dependent manner. Silencing betaTrCP1 augments FOXO3 protein level, resulting in promoting cellular apoptosis in cancer cells. In animal models, increasing FOXO3 protein level by silencing betaTrCP1 suppresses tumorigenesis, whereas decreasing FOXO3 by over-expressing betaTrCP1 promotes tumorigenesis and tumor growth in vivo.This is a unique demonstration that the betaTrCP1-mediated FOXO3 degradation plays a crucial role in tumorigenesis. These findings significantly contribute to understanding of the control of FOXO3 stability in cancer cells and may provide opportunities for developing innovative anticancer therapeutic modalities

Wildfires offset the increasing but spatially heterogeneous Arctic–boreal CO₂ uptake

The Arctic–Boreal Zone is rapidly warming, impacting its large soil carbon stocks. Here we use a new compilation of terrestrial ecosystem CO2 fluxes, geospatial datasets and random forest models to show that although the Arctic–Boreal Zone was overall an increasing terrestrial CO2 sink from 2001 to 2020 (mean ± standard deviation in net ecosystem exchange, −548 ± 140 Tg C yr−1; trend, −14 Tg C yr−1; P &lt; 0.001), more than 30% of the region was a net CO2 source. Tundra regions may have already started to function on average as CO2 sources, demonstrating a shift in carbon dynamics. When fire emissions are factored in, the increasing Arctic–Boreal Zone sink is no longer statistically significant (budget, −319 ± 140 Tg C yr−1; trend, −9 Tg C yr−1), and the permafrost region becomes CO2 neutral (budget, −24 ± 123 Tg C yr−1; trend, −3 Tg C yr−1), underscoring the importance of fire in this region.</p