The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling

Abstract

De-ubiquitinating enzymes (DUBs) can reverse the modifications catalyzed by ubiquitin ligases and as such are believed to be important regulators of a variety of cellular processes. Several members of this protein family have been associated with human cancers; however, there is little evidence for a direct link between deregulated de-ubiquitination and neoplastic transformation. Ubiquitin C-terminal hydrolase (UCH)-L1 is a DUB of unknown function that is overexpressed in several human cancers, but whether it has oncogenic properties has not been established. To address this issue, we generated mice that overexpress UCH-L1 under the control of a ubiquitous promoter. Here, we show that UCH-L1 transgenic mice are prone to malignancy, primarily lymphomas and lung tumors. Furthermore, UCH-L1 overexpression strongly accelerated lymphomagenesis in Eμ-myc transgenic mice. Aberrantly expressed UCH-L1 boosts signaling through the Akt pathway by downregulating the antagonistic phosphatase PHLPP1, an event that requires its de-ubiquitinase activity. These data provide the first in vivo evidence for DUB-driven oncogenesis and suggest that UCH-L1 hyperactivity deregulates normal Akt signaling.

Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease

“…However, there was also a slight decrease in the p27 levels in the UCHL1 -/-mice with >50 μM suggesting potential off-target effects of the inhibitor in the absence of the UCHL1 protein potentially due to effects on the UCHL1 systemic isoform UCHL3 which is ubiquitously expressed and may have opposing roles. A role for UCHL1 in proliferation is consistent with the pro-oncogenic functions of UCHL1 in various cancers [34] and the findings that in lymphoma cells UCHL1 knockdown decreases cellular growth and viability [30]. Although we observe reduced proliferation in UCHL1 -/-HSC their viability was not reduced in comparison with WT HSC ( Supplementary Fig.…”

“…Therefore, the function of UCHL1 is likely to vary widely in a cell and environment specific manner. Indeed, diverse roles are described in kidney disease, neurodegeneration and cancer where UCHL1 exerts its effects by influencing levels of free proteins such as cellular Ub, glutathione and by regulation of the cell cycle [13,[29][30][31][32][33]. In accordance with this, following our expression analysis we went on to show that UCHL1 is involved in the post-translational control of the cell cycle protein Rb and in the proliferative response of aHSC to PDGFBB.…”

Role of Growth Arrest and DNA Damage–inducible α in Akt Phosphorylation and Ubiquitination after Mechanical Stress-induced Vascular Injury

“…More surprising, we found evidence of K48-linked ubiquitination of Akt associated with GADD45a depletion with proteasomal inhibition (MG132) restoring Akt levels in GADD45a-silenced EC. These effects are mediated by UCHL1, a DUB known to be silenced in a variety of cancers (20,29,30) and implicated in the pathogenesis of Parkinson disease (31) but only recently linked to effects on Akt signaling (32). Our results now extend these previous findings and demonstrate for the first time evidence that total Akt expression levels are mediated directly by UCHL1.…”

UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma

“…2,3 Through an unbiased activity screen of deubiquitinating enzymes in a variety of cancers, we uncovered frequent overexpression of the neuroendocrine-specific enzyme UCH-L1 in mature B-cell cancers including Burkitt lymphoma and DLBCL. 4,5 We subsequently found transgenic Uchl1 drives the development of spontaneous lymphoma in mice, demonstrating its oncogenic activity. 5 Mechanistically, UCH-L1 plays a novel role in regulating mammalian target of rapamycin (mTOR)-AKT signaling, a pathway important in GCB and lymphoma development.…”