c-Abl Regulates Proteasome Abundance by Controlling the Ubiquitin-Proteasomal Degradation of PSMA7 Subunit

Li, Dapei; Dong, Qincai; Tao, Qingping; Gu, Jie; Cui, Yan; Jiang, Xuefeng; Yuan, Jing; Li, Weihua; Xu, Rao; Jin, Yu; Li, Ping; Weaver, David T.; Ma, Qingjun; Li, Xuan; Cao, Cheng

doi:10.1016/j.celrep.2014.12.044

Cited by 31 publications

(41 citation statements)

References 47 publications

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“…Overexpression of α4-Flag resulted in increased levels of cellular proteasome activity (Figs. 5A and 5B), as observed previously (Li et al, 2015). Overexpression of α4 also resulted in increased levels of 26S and 20S proteasomes (Figs.…”

Section: Resultssupporting

confidence: 88%

“…Interestingly, the related cytoplasmic tyrosine kinases ABL and ARG were recently reported to reduce degradation of α4 protein and thereby promote its accumulation (Li et al, 2015). This was accompanied by an increase in total proteasome levels and proteolytic capacity of the cells (Li et al, 2015) (see Fig. S5B).…”

Section: Resultsmentioning

confidence: 99%

“…The tumor suppressor protein BRCA1 was previously identified as a ubiquitin ligase that targets free α4 for proteasome-mediated degradation (Li et al, 2015). Correspondingly, we found that co-expression of BRCA1 with α4-CC-Flag in HEK293T cells resulted in decreased levels of α4-α4 proteasomes (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

2016

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Summary Targeted intracellular protein degradation in eukaryotes is largely mediated by the proteasome. Here we report formation of an alternative proteasome isoform in human cells, previously found only in budding yeast, which bears an altered subunit arrangement in the outer ring of the proteasome core particle. These proteasomes result from incorporation of an additional α4 (PSMA7) subunit in the position normally occupied by α3 (PSMA4). Assembly of ‘α4-α4’ proteasomes depends on the relative cellular levels of α4 and α3, and on the proteasome assembly chaperone PAC3. The oncogenic tyrosine kinases ABL and ARG and the tumor suppressor BRCA1 regulate cellular α4 levels and formation of α4-α4 proteasomes. Cells primed to assemble α4-α4 proteasomes exhibit enhanced resistance to toxic metal ions. Taken together, our results establish the existence of a novel mammalian proteasome isoform and suggest a potential role in enabling cells to adapt to environmental stresses.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

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Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

2016

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“…However, a more recent paper (Li et al, 2015) shows that Arg and c-Abl, through the phosphorylation of proteasome subunit PSMA7, also induce an inhibition of proteasome degradation. Based on these new literature data, Arg silencing might result in a degradation of the proteasome that is unbalanced by an increase of its activity.…”

Section: Discussionmentioning

confidence: 99%

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Torsello

Bianchi

Meregalli

et al. 2016

Journal of Cell Science

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Renal tubular cells are involved in the tubular interstitial fibrosis observed in diabetic nephropathy. It is debated whether epithelialmesenchymal transition (EMT) affects tubular cells, which under highglucose conditions overproduce transforming growth factor-β (TGF-β), a fibrogenic cytokine involved in interstitial fibrosis development. Our study investigated the involvement of non-receptor tyrosine kinase Arg (also called Abl2) in TGF-β production. Human primary tubular cell cultures exposed to high-glucose conditions were used. These cells showed an elongated morphology, stress fibers and vimentin increment but maintained most of the epithelial marker expression and distribution. In these cells exposed to high glucose, which overexpressed and secreted active TGF-β1, Arg protein and activity was downregulated. A further TGF-β1 increase was induced by Arg silencing with siRNA, as with the Arg tyrosine kinase inhibitor Imatinib. In the cells exposed to high glucose, reactive oxygen species (ROS)-dependent Arg kinase downregulation induced both RhoA activation, through p190RhoGAPA (also known as ARHGAP35) modulation, and proteasome activity inhibition. These data evidence a new specific involvement of Arg kinase into the regulation of TGF-β1 expression in tubular cells under high-glucose conditions and provide cues for new translational approaches in diabetic nephropathy.

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“…Growing evidence suggests that diverse mechanisms, including post-translational modifications, underlie these activities. For example, phosphorylation of the proteasome subunit PSMA7 by cAbl kinase impacts its regulation by BRCA1, which controls PSMA7 ubiquitination and stability 173 . Both BRCA1 and cAbl are deregulated in cancer, suggesting that deregulated PSMA7 activity may function in oncogenesis.…”

Section: Regulation By Alternative Splicingmentioning

confidence: 99%

Dysregulation of ubiquitin ligases in cancer

Ronai

2015

Drug Resistance Updates

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Ubiquitin ligases are critical components of the ubiquitin proteasome system (UPS), which governs fundamental processes regulating normal cellular homeostasis, metabolism, and cell cycle in response to external stress signals and DNA damage. Among multiple steps of the UPS system required to regulate protein ubiquitination and stability, UBLs define specificity, as they recognize and interact with substrates in a temporally- and spatially-regulated manner. Such interactions are required for substrate modification by ubiquitin chains, which marks proteins for recognition and degradation by the proteasome, or alters their subcellular localization or assembly into functional complexes. UBLs are often deregulated in cancer, altering substrate availability or activity in a manner that can promote cellular transformation. Such deregulation can occur at the epigenetic, genomic, or post-translational levels. Alterations in UBL can be used to predict their contributions, affecting tumor suppressors or oncogenes in select tumors. Better understanding of mechanisms underlying UBL expression and activities is expected to drive the development of next generation modulators that can serve as novel therapeutic modalities. This review summarizes our current understanding of UBL deregulation in cancer and highlights novel opportunities for therapeutic interventions.

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c-Abl Regulates Proteasome Abundance by Controlling the Ubiquitin-Proteasomal Degradation of PSMA7 Subunit

Cited by 31 publications

References 47 publications

Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

Assembly of an Evolutionarily Conserved Alternative Proteasome Isoform in Human Cells

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Dysregulation of ubiquitin ligases in cancer

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