Targeting Protein–Protein Interactions in the Ubiquitin–Proteasome Pathway

Gaczyńska, Maria; Osmulski, Paweł A.

doi:10.1016/bs.apcsb.2017.09.001

Cited by 16 publications

(14 citation statements)

References 197 publications

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“…Target proteins are initially recognized by upstream components and tagged with polyubiquitin chains. Then these polyubiquitinated proteins are send to 26S proteasome for degradation [24]. Many proteins that are regulated by ubiquitylation control cellular processes, such as apoptosis, cell-cycle progression and gene transcription that are relevant to tumorigenesis [25].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA

Lu¹,

Yin²,

Zhang³

et al. 2019

Cancer Cell Int

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Background NPL4 is an important cofactor of the valosin-containing protein (VCP)–NPL4–UFD1 complex. The VCP–NPL4–UFD1 has been considered as a ubiquitin proteasome system (UPS) regulator and response to protein degradation. While NPL4 plays important roles in various diseases, little is known about its functions in bladder cancer (BC). Methods MTT assays and colony forming test were performed to evaluate cell proliferation ability and Western blotting was used to detect protein expression. Cyclin D1 mRNA expression was detected using qRT-PCR, and coimmunoprecipitation (CoIP) was used to detect protein–protein interactions. Results NPL4 was upregulated in BC tissue and correlated with poor prognosis. Upregulation of NPL4 promoted cell proliferation while suppression of NPL4 reduced BC cell proliferation. Upregulation of NPL4 led to overexpression of cyclin D1 by enhancing its mRNA stability. Moreover, NPL4 was found to bind directly to DXO and induce its degradation. DXO was downregulated in BC tissue and regulated BC cell proliferation by destabilizing cyclin D1 mRNA. DXO-mediated NPL4 regulated BC cell proliferation by stabilizing cyclin D1 expression. Conclusions The NPL4/DXO/cyclin D1 axis exert crucial role in BC cell growth and is associated with prognosis and may represent a potential therapeutic target for BC.

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Section: Discussionmentioning

confidence: 99%

Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA

Lu¹,

Yin²,

Zhang³

et al. 2019

Cancer Cell Int

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“…degradation (16). The 26S proteasome is an essential multi-catalytic protease complex, which serves key roles in the function of the UPP.…”

Section: Oxaliplatin Promotes Simad2l2-induced Apoptosis In Colon Cancer Cellsmentioning

confidence: 99%

Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells

Zhao

et al. 2021

Mol Med Rep

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The clinical efficacy of colorectal tumor treatment is restricted due to platinum agent resistance. Translesion DNA synthesis (TLS) has been shown to contribute to this resistance; however, the exact molecular mechanism remains unknown. The present study aimed to investigate the possible function of the core of the TLS polymerase mitotic arrest deficient 2 like 2 (MAD2L2) in drug sensitivity, in order to provide a treatment rationale for platinum-based chemotherapy in colon cancer. In the present study, MAD2L2 was knocked down using MAD2L2-specific small interfering (si)RNA. HCT116 and SW620 cells were treated with oxaliplatin and MG132; oxaliplatin is a platinum compound that induces DNA damage and MG132 is a potent proteasome inhibitor. Cell viability was determined using an MTT assay. Cell apoptosis was examined via flow cytometry and TUNEL assay. The activity of proteasome 26S subunit, non-ATPase 13 (PSMD13) was detected using ELISA, while the expression levels of apoptotic-related proteins were detected via western blotting. The results demonstrated that cells treated with oxaliplatin or MG132 alone had decreased viability, but a synergistic effect was not observed after co-treatment. In addition, the knockdown of MAD2L2 caused by siMAD2L2 or oxaliplatin treatment increased the expression levels of the pro-apoptotic proteins Bax and Bak and decreased the expression levels of the anti-apoptotic protein Bcl-2, compared with the negative control group. Moreover, MG132 alleviated the decrease in MAD2L2 expression, while reducing siMAD2L2-induced cell apoptosis. These results indicate that oxaliplatin promotes siMAD2L2-induced apoptosis in colon cancer cells. This process was associated with the Bcl-2 and ubiquitin-proteasome pathway. Overall, the present study provides a theoretical basis for improving the clinical efficacy of colon cancer by combining chemotherapy and gene therapy.

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“…These pockets are established allosteric hotspots and specific binding sites not only for the REG activator but most importantly for the Rpt (Regulatory Particle ATP-ase) subunits of the 19S component of 26S proteasome. This holoenzyme is the most advanced and physiologically involved among assemblies sharing the 20S proteasome catalytic core [28]. Beyond their proteasome-binding capacity, TAT peptides have a strong cell-penetrating potential: a fragment nearly identical to TAT1, 47 Y-R 57 , was previously reported as a "cell-penetrating-peptide" with high blood-brain barrier (BBB)-passing capacity due to its structure and highly positive charge [29].…”

Section: Design Of Tat Peptidesmentioning

confidence: 99%

“…However, the fact that only ChT-L and not the other two proteasomal peptidases are activated by TAT peptides (Figures 3 and 4) also points at the possible role of allosteric signaling. Indeed, proteins, peptides or small molecules targeting the α face may in vitro affect one or more peptidases [28]. Explanation of the diverse effects may involve a direct signaling between the α face pockets and catalytic chamber, between the gate and catalytic chamber, or all the former plus inter-catalytic sites allosteric loops [47,48].…”

Section: Molecules 2019 24 X For Peer Review 6 Of 17mentioning

confidence: 99%

New Peptide-Based Pharmacophore Activates 20S Proteasome

et al. 2020

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The proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively unexplored. In this work, we introduce short TAT peptides derived from HIV-1 Tat protein and modified with synthetic turn-stabilizing residues as proteasome agonists. Molecular docking and biochemical studies point to the α1/α2 pocket of the core proteasome α ring as the binding site of TAT peptides. We postulate that the TATs’ pharmacophore consists of an N-terminal basic pocket-docking “activation anchor” connected via a β turn inducer to a C-terminal “specificity clamp” that binds on the proteasome α surface. By allosteric effects—including destabilization of the proteasomal gate—the compounds substantially augment activity of the core proteasome in vitro. Significantly, this activation is preserved in the lysates of cultured cells treated with the compounds. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use.

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Targeting Protein–Protein Interactions in the Ubiquitin–Proteasome Pathway

Cited by 16 publications

References 197 publications

Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA

Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA

Oxaliplatin promotes siMAD2L2‑induced apoptosis in colon cancer cells

New Peptide-Based Pharmacophore Activates 20S Proteasome

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