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TGF-? upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability.

ABSTRACT: Crosstalk between transforming growth factor beta (TGF-?) signaling and p53 has a critical role in cancer progression. TGF-? signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-? signaling. However, it remains unknown whether p53 stability is regulated by TGF-?. In the current study, we identify that USP15 binds to and stabilizes p53 through deubiquitination in U2OS and HEK293 cells. TGF-? promotes the translation of USP15 through activation of mammalian target of rapamycin by the phosphoinositide 3-kinase/AKT pathway. Upregulation of USP15 translation links the crosstalk between TGF-? signaling and p53 stability, allowing this cytokine to have a critical role in cancer progression.

SUBMITTER: Liu WT

PROVIDER: S-EPMC5442427 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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TGF-β upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability.

Liu W-T WT Huang K-Y KY Lu M-C MC Huang H-L HL Chen C-Y CY Cheng Y-L YL Yu H-C HC Liu S-Q SQ Lai N-S NS Huang H-B HB

Oncogene 20161128 19

Crosstalk between transforming growth factor beta (TGF-β) signaling and p53 has a critical role in cancer progression. TGF-β signals via Smad and non-Smad pathways. Under normal conditions, wild-type p53 forms a complex with Smad2/3 and co-activates transcription of a variety of tumor suppressor genes, resulting in tumor suppressive effects. Thus, p53 stability is essential in progression of tumor suppressive responses mediated by TGF-β signaling. However, it remains unknown whether p53 stabilit ...[more]

PMID: 27893708

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Project description:BackgroundThe transforming growth factor-β (TGF-β) signaling pathway plays an essential role in maintaining homeostasis in joints affected by osteoarthritis (OA). However, the specific mechanism of non-SMAD and classical SMAD signaling interactions is still unclear, which needs to be further explored.MethodsIn ATDC5 cells, USP15 overexpression and knockout were performed using the transfected lentivirus USP15 and Crispr/Cas9. Western blotting and immunofluorescence staining were used to test p-SMAD2 and cartilage phenotype-related molecular markers. In rat OA models, immunohistochemistry, hematoxylin and eosin (HE)/Safranin-O fast green staining, and histology were used to examine the regulatory activity of USP15 in TGF-β/SMAD2 signaling and the cartilage phenotype. Then, ERK2 overexpression and knockout were performed. The expressions of USP15, p-SMAD2, and the cartilage phenotype were evaluated in vitro and in vivo. To address whether USP15 is required for ERK2 and TGF-β/SMAD2 signaling, we performed rescue experiments in vitro and in vivo. Immunoprecipitation and deubiquitination assays were used to examine whether USP15 could bind to ERK2 and affect the deubiquitination of ERK2. Finally, whether USP15 regulates the level of p-ERK1/2 was evaluated by western blotting, immunofluorescence staining, and immunohistochemistry in vitro and in vivo.ResultsOur results indicated that USP15 stimulated TGF-β/SMAD2 signaling and the cartilage phenotype. Moreover, ERK2 required USP15 to influence TGF-β/SMAD2 signaling for regulating the cartilage phenotype in vivo and in vitro. And USP15 can form a complex with ERK2 to regulate ubiquitination of ERK2. Interestingly, USP15 did not regulate the stability of ERK2 but increased the level of p-ERK1/2 to further enhance the TGF-β/SMAD2 signaling pathway.ConclusionsTaken together, our study revealed positive feedback regulation between USP15 and ERK2, which played a critical role in TGF-β/SMAD2 signaling to inhibit OA progression. Therefore, this specific mechanism can guide the clinical treatment of OA.

Dataset Information

TGF-? upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability.

Publications

TGF-β upregulates the translation of USP15 via the PI3K/AKT pathway to promote p53 stability.

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