Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis

Wang, Siyu; Juan, Jiaxiang; Zhang, Zubin; Du, Yanyun; Xu, Yujia; Tong, Jiefei; Cao, Biyin; Moran, Michael F.; Zeng, Yuanying; Mao, Xinliang

doi:10.1038/cddis.2017.450

Cited by 69 publications

(89 citation statements)

References 23 publications

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“…In breast cancer, TMEPAI promotes breast cancer cell proliferation by converting TGF-β from a tumor suppressor to a tumor promoter (5), while in lung cancer cells, TMEPAI sequestrates R-SMAD and downregulates PTEN therefore enhancing the PI3K/AKT signaling pathway (3). In our present study, TMEPAI-induced MM cell apoptosis is probably associated with c-Maf ubiquitination and degradation because c-Maf promotes MM cell survival while silencing c-Maf leads to MM cell apoptosis (19). Moreover, TMEPAI is markedly downregulated in MM cells but highly expressed in bone marrow cells from healthy donors.…”

Section: Discussionmentioning

confidence: 69%

“…Because c-Maf is a transcription factor, we next evaluated to whether TMEPAI modulated c-Maf transcriptional activity. To this end, a luciferase construct directed by MARE (Maf recognition element) (19) was co-transfected with wild-type or ΔTM-TMEPAI. The luciferase activity analysis revealed that ΔTM-TMEPAI lost its modularity on the stability and transcriptional activity of c-Maf (Fig.…”

Section: The Transmembrane Domain Is Indispensable For Tmepai-mediatementioning

confidence: 99%

“…The NEDD4 gene was first cloned from the genomic DNA of MM cell line RPMI-8226 and it was then subcloned into pcDNA3.1 vector with a Myc tag. The luciferase reporter driven by Maf Recognition Element (MARE, 5'-TGCGAGTGAGGCA-3') (pGL4-MARE.Luci) was cloned as described previously (19). The PY motif mutants of TMEPAI were cloned by site-directed mutagenesis using the following primers: 5'-CCCCCACCCGCCCAGGGCCCCTG CACCCTCCAGCTT-3' (Forward) and 5'-GCCCTGGGCGGGTGGGGGCTCCTCC CCGTCTGACAG-3' (Reverse) for the PY1 mutant, 5'-CCGCCCACCGCCAGCGAGGTCAT CGGCCACTACCCG-3' (forward) and 5'-ACCTCGCTGGCGGTGGGCGGCGG CCCCTCCATGCG-3' (Reverse) for the PY2 mutant.…”

Section: Antibodies and Plasmidsmentioning

confidence: 99%

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The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

Liu

et al. 2018

Journal of Biological Chemistry

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Transmembrane prostate androgen-induced protein (TMEPAI, also called prostate transmembrane protein, androgen induced 1 [PMEPA1]), is a type I transmembrane (TM) protein, but its cellular function is largely unknown. Here, studying factors influencing the stability of c-Maf, a critical transcription factor in multiple myeloma (MM), we found that TMEPAI induced c-Maf degradation. We observed that TMEPAI recruited neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), a WW domain-containing ubiquitin ligase, to c-Maf, leading to its degradation through the proteasomal pathway. Further investigation revealed that TMEPAI interacts with NEDD4 via its conserved PY motifs. Alanine substitution or deletion of these motifs abrogated the TMEPAI complex formation with NEDD4, resulting in failed c-Maf degradation. Functionally, TMEPAI suppressed the transcriptional activity of c-Maf. Of note, increased TMEPAI expression was positively associated with the overall survival of MM patients. Moreover, (1). In addition to androgen, TMEPAI expression is also stimulated by some growth factors such as epidermal growth factor (EGF) and transforming growth factor-β (TGF-β) (2). The expression profiling found that TMEPAI is overexpressed in solid cancers including prostate cancer , lung (3,4), breast (3,5) and ovarian cancers (6), and rental cell carcinoma (7), but it is not detectable in liquid cancers such as leukemia and lymphoma samples (7). The specific expression pattern suggests that TMEPAI might function differently upon specific cancer types. For example, TMEPAI displays as a tumor suppressor in prostate cancer progression because silence of TMEPAI leads to accelerated proliferation of prostate cancer cells (8) while expression of TMEPAI inhibits prostate cancer cell growth (9) and prevents its bone metastasis (10). However, TMEPAI acts as an oncogene and promotes proliferation and survival of lung and breast cancers. TMEPAI mediates the degradation of receptor-activated SMAD and activates non-canonical PI3K/AKT signaling transduction thus promoting TGF-β-dependent cell growth and metastasis of triple negative breast cancer (3). In lung cancer cells, TMEPAI not only increases cancer cell proliferation, migration and invasion (11,12) but also enhances tumorigenicity and the epithelial-mesenchymal transition (EMT) of lung cancer cells (4). These actions were associated with TMEPAI-induced TGF-β degradation in lysosomes and TMEPAI-induced reactive oxygen species and insulin receptor substrate-1 (4). In contrast, knockdown of TMEPAI enhances Smad2 phosphorylation and significantly suppressed lung cancer cell proliferation in the presence of TGF-β. All the above results collectively suggest that TMEPAI can promote or suppress cancer cell proliferation and tumor growth depending on the cancer types but the TGF-β signaling pathway is a key factor.Hematological malignancies are a collection of blood cancers including leukemia, lymphoma and multiple myeloma in which TMEPAI is less expressed (7), but the fun...

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Section: Discussionmentioning

confidence: 69%

Section: The Transmembrane Domain Is Indispensable For Tmepai-mediatementioning

confidence: 99%

Section: Antibodies and Plasmidsmentioning

confidence: 99%

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The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

Liu

et al. 2018

Journal of Biological Chemistry

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“…USP5 has been associated with tumorigenesis [15][16][17][18][19] , neurodegeneration [20][21][22] , and viral infections 23,24 . In addition, USP5 plays a role in regulation of ubiquitin levels in DNA damage repair 25 and stress granules 26 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

Mann

Franzoni

Freitas

et al. 2019

Preprint

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USP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve ubiquitin-specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signalling pathways in health and disease. Corresponding Authors Author Contributions M.M. and M.S. wrote the manuscript. I.F. and R.F.F. completed preliminary docking studies. R.H., and M.M. performed the crystallographic calculations and model refinement for X-ray crystal structures with 1, 5, and 7. W.T. performed the crystallographic calculations and model refinement of X-ray structure with compound 21. M.M. and S.H tested compounds. M.M. completed hit expansion. C.H.A, R.H. and M.S. advised throughout the project. Notes:The authors declare no competing financial interest.

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“…[19][20][21] As a member of the USPs family, USP5 can play the role of deubiquitination enzyme by hydrolyzing ubiquitin chain. 24,25 Wang et al 26 found that inhibiting the expression of deubiquitinase USP5 could lead to degradation of c-Maf protein and induce apoptosis of MM cells. 24,25 Wang et al 26 found that inhibiting the expression of deubiquitinase USP5 could lead to degradation of c-Maf protein and induce apoptosis of MM cells.…”

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confidence: 99%

RETRACTED: miR‐125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5

Wu¹,

Zhang²,

Chen³

et al. 2019

J of Cellular Biochemistry

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miR‐125a is a microRNA that is frequently diminished in various human malignancies. However, the mechanism by which impaired miR‐125a promotes cancer growth remains undefined. In this study, we investigated the role of miR‐125a in the proliferation and apoptosis of multiple myeloma (MM). To do this, we used MM tissue samples (from 40 anonymous patients), normal matched control samples, and five MM‐derived cell lines. We also established a mouse model of MM xenograft to explore the effect of overexpression of miR‐125a on the MM growth in vivo. Quantitative real‐time polymerase chain reaction revealed that the miR‐125a expression was broadly reduced in MM tissues and cell lines. The impairment of miR‐125a in MM tissues was functionally relevant because the overexpression of miR‐125a remarkably decreased the cell viability and colony‐forming activity, at least in part, by promoting apoptosis in two miR‐125a‐deficient MM cell lines: NCI‐H929 and U266. Interestingly, we also discovered that the human gene encoding the ubiquitin‐specific peptidase 5 (USP5), which is known to promote cellular deubiquitination and ubiquitin/proteasome‐dependent proteolysis, was a direct transcriptional target for miR‐125a to repress. More importantly, the heterologous expression of USP5 significantly reversed the growth‐inhibitory effects of miR‐125a on MM cells in vitro. In the mouse xenograft model, overexpressed miR‐125a prominently inhibited the growth of MM tumors and concomitantly reduced the expression of USP5 in tumor tissues. These results suggest that miR‐125a inhibits the expression of USP5, thereby mitigating the proliferation and survival of malignant MM cells. We propose that USP5 acts as an oncoprotein in miR‐125a‐missing cancers.

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Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis

Cited by 69 publications

References 23 publications

The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

The transmembrane protein TMEPAI induces myeloma cell apoptosis by promoting degradation of the c-Maf transcription factor

Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

RETRACTED: miR‐125a suppresses malignancy of multiple myeloma by reducing the deubiquitinase USP5

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