Molecular modulation of the copper and cisplatin transport function of CTR1 and its interaction with IRS-4

Tsai, Cheng‐Yu; Larson, Christopher; Safaei, Roohangiz; Howell, Stephen B.

doi:10.1016/j.bcp.2014.06.019

Cited by 20 publications

(15 citation statements)

References 54 publications

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“…We submitted those CTR1‐associated proteins for mass spectrometry analysis in order to find ubiquitin‐associated proteins, which would likely be the targets of EZH2. However, like Tsai et al, the E3 ligase of CTR1 was still not determined due to a noisy background created by cellular reactions to cDDP. Although we failed to tease out the CTR1‐specific E3 ligase in cDDP‐treated samples, we identified a series of depleted pathways for protein synthesis and metabolism (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

et al. 2018

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Enhancer of zeste homolog 2 (EZH2), which is overexpressed in a wide range of tumors, contributes to ovarian cancer malignancy in several different ways. We aimed to illustrate the role of EZH2 in ovarian cancer cisplatin resistance and to identify possible underlying mechanisms of this role that may provide a rationale for targeting EZH2 in cancer treatment. Here, we present data indicating that EZH2 overexpression is associated with cisplatin resistance and intracellular platinum drug accumulation. Measurements of EZH2 in 84 ovarian cancer patients suggested that patients with high EZH2 levels tend to have poor responses to cisplatin. The EZH2 level progressively increased in cells receiving repeated cisplatin exposure. Downregulation of EZH2 not only sensitized cellular reactions to cisplatin and increased cellular platinum accumulation when cells were exposed to both cisplatin and BODIPY‐Pt (a fluorescent cisplatin complex) but also protected copper transporter 1, a high‐affinity copper transporter closely related to cisplatin resistance, from cisplatin‐induced proteasomal degradation. Overall, these findings identify a new mechanism that expands the unrecognized role of EZH2 in ovarian cancer cisplatin resistance.

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Section: Discussionmentioning

confidence: 99%

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

et al. 2018

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“…CTR1 contains a potential μ2-binding motif, YNSM, in its cytoplasmic loop. Mutations in this motif of CTR1 showed decreased CTR1 internalization (Tsai et al, 2014). It seems likely that the YNSM motif in CTR1 might be the site for μ2 binding.…”

Section: Discussionmentioning

confidence: 97%

Dynamic internalization and recycling of a metal ion transporter: Cu homeostasis and CTR1, the human Cu+ uptake system

Clifford

Maryon

Kaplan

2016

Journal of Cell Science

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Cu ion (Cu) entry into human cells is mediated by CTR1 (also known as SLC31A1), the high-affinity Cu transporter. When extracellular Cu is raised, the cell is protected against excess accumulation by rapid internalization of the transporter. When Cu is lowered, the transporter returns to the membrane. We show in HEK293 cells overexpressing CTR1 that expression of either the C-terminal domain of AP180 (also known as SNAP91), a clathrin-coat assembly protein that sequesters clathrin, or a dominant-negative mutant of dynamin, decreases Cu-induced endocytosis of CTR1, as does a dynamin inhibitor and clathrin knockdown using siRNA. Utilizing imaging, siRNA techniques and a new high-throughput assay for endocytosis employing CLIP-tag methodology, we show that internalized CTR1 accumulates in early sorting endosomes and recycling compartments (containing Rab5 and EEA1), but not in late endosomes or lysosomal pathways. Using live cell fluorescence, we find that upon extracellular Cu removal CTR1 recycles to the cell surface through the slowerrecycling Rab11-mediated pathway. These processes enable cells to dynamically alter transporter levels at the plasma membrane and acutely modulate entry as a safeguard against excess cellular Cu.

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“…OVCAR8 ovarian cancer cells were obtained from Dr. Tom Hamilton, Fox Chase Cancer Center and cultured in RPMI 1640 medium (HyClone; Logan, UT) supplemented with 10 % fetal bovine serum at 37 °C, 5 % CO 2 . The wild-type myc-tagged hCTR1 was constructed in the vector pENTR/D-TOPO and then transferred to the pLenti6/V5-DEST by LR reaction as previously described 37 . The myc-CTR1 WT lentiviral particles were produced in HEK293T cells using the ViraPower ™ packaging kit (Invitrogen; Carlsbad, CA) and then transduced into the HEK293T and OVCAR8 CTR1 KO-1 and CTR1 KO-2 cells under 8 μg/mL blasticidin selection.…”

Section: Methodsmentioning

confidence: 99%

“…The plasma membrane localization of CTR1 was measured by cell surface biotinylation as previous reported 37 .…”

Section: Methodsmentioning

confidence: 99%

The copper transporter 1 (CTR1) is required to maintain the stability of copper transporter 2 (CTR2)

et al. 2015

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Mammalian cells have two influx Cu transporters that form trimers in membranes. CTR1 is the high affinity transporter that resides largely in the plasma membrane, and CTR2 is the low affinity transporter that is primarily associated with vesicular structures inside the cell. The major differences between CTR1 and CTR2 are that CTR1 contains a HIS/MET-rich domain N-terminal of the METS that participate in the first two stacked rings that form the pore, and a longer C-terminal tail that includes a Cu binding HIS-CYS-HIS (HCH) motif right at the end. It has been reported that CTR1 and CTR2 are physically associated with each other in the cell. We used the CRISPR-Cas9 technology to knock out either CTR1 or CTR2 in fully malignant HEK293T and OVCAR8 human ovarian cancer cells to investigate the interaction of CTR1 and CTR2. We report here that the level of CTR2 protein is markedly decreased in CTR1 knockout clones while the CTR2 transcript level remains unchanged. CTR2 was found to be highly ubiquitinated in the CTR1 knock out cells, and inhibition of the proteosome prevented the degradation of CTR2 when CTR1 was not present while inhibition of autophagy had no effect. Re-expression of CTR1 rescued CTR2 from degradation in the CTR1 knockout cells. We conclude that CTR1 is essential to maintain the stability of CTR2 and that in the absence of CTR1 CTR2 is degraded by the proteosome. This reinforces the concept that the functions of CTR1 and CTR2 are inter-dependent within the Cu homeostasis system.

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Molecular modulation of the copper and cisplatin transport function of CTR1 and its interaction with IRS-4

Cited by 20 publications

References 54 publications

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

Dynamic internalization and recycling of a metal ion transporter: Cu homeostasis and CTR1, the human Cu+ uptake system

The copper transporter 1 (CTR1) is required to maintain the stability of copper transporter 2 (CTR2)

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