No abstract

Here we report that mice deficient for the proteasome activator, REGg, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGg in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGg elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGg promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGg activates Wnt/b-catenin signalling by degrading GSK-3b in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of b-catenin. Conversely, MAPK/p38 inactivation or REGg deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGg acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/b-catenin pathway.

Background Hyper-activation of TGF-β signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-β pathway in HCC, especially at the post-translational level, are not well understood. Methods Associations of deubiquitinase POH1 with TGF-β signaling activity and the outcomes of HCC patients were examined by data mining of online HCC datasets, immunohistochemistry analyses using human HCC specimens, spearman correlation and survival analyses. The effects of POH1 on the ubiquitination and stability of the TGF-β receptors (TGFBR1 and TGFBR2) and the activation of downstream effectors were tested by western blotting. Primary mouse liver tissues from polyinosinic:polycytidylic acid (poly I:C)- treated Mx-Cre+, poh1 f/f mice and control mice were used to detect the TGF-β receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice. Findings Here we show that POH1 is a critical regulator of TGF-β signaling and promotes tumor metastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-β response, metastatic potential and outcomes, reveal that POH1 expression positively correlates with activities of TGF-β signaling in tumors and with malignant disease progression. Functionally, POH1 intensifies TGF-β signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo . The expression of the TGF-β receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-β receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-β receptors. Conclusion Our study highlights the pathological significance of aberrantly expressed POH1 in TGF-β signaling hyperactivation and aggressive progression in HCC.