CACUL1/CAC1 Regulates the Antioxidant Response by Stabilizing Nrf2

Kigoshi, Yu; Fukuda, Tomomi; Endo, Tomoyuki; Hayasaka, Nami; Iemura, Shun‐ichiro; Natsume, Tohru; Tsuruta, Fuminori; Chiba, Tomoki

doi:10.1038/srep12857

Cited by 7 publications

(6 citation statements)

References 58 publications

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“…Our previous studies found that Helicobacter and deoxycholic acid could promote the expression of CACUL1 and promote the proliferation and metastasis of tumor cells [20][21][22]. Our study also found that CACUL1 was highly expressed in GBC.…”

supporting

confidence: 74%

“…The activity of Nrf2 was tightly regulated at basal levels through its ubiquitination by Cul3-Keap1 and consequential degradation. Upon exposure to stress, the Cul3-Keap1 ligase is inhibited by CACUL1, leading to Nrf2 stabilization and activation [21]. Therefore, we speculated that CACUL1 promotes ITGBL1 expression through NRF2.…”

Section: Cacul1 Upregulated the Expression Of Itgbl1 Through Nrf2mentioning

confidence: 97%

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Abnormal Inflammatory Status Promotes Lymphatic Metastasis of Gallbladder Cancer Cells Through the CACUL1/NRF2/ITGBL1/ITGA9/VEGF-C Pathway

Kong¹,

Wang²,

Suo³

2021

Preprint

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Background: Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis, but the aetiology is poorly understood. Long standing gallstone and chronic inflammation had been observed to be risk factors for GBC. Gallstone and chronic infection may lead to increased turnover of primary bile acids to secondary bile acids and inflammatory cytokines, which were known tumor promoters and might be responsible for GBC. But the exact molecular mechanism was not fully understood. Results: Our results showed that gallstones and chronic infection could increase the levels of inflammatory cytokines, and promoted the expression of CACUL1 and ITGBL1. Our study furtherly identified the highly expressed patients of CACUL1 and ITGBL1 had a poor prognosis, and them therefore might serve as a potential prognostic biomarker for GBC patients. CACUL1 promoted the expression of ITGBL1 through NRF2. Furthermore, ITGBL1 promoted the migration and invasion of GBC cells. In addition, ITGBL1 was found to induce lymphangiogenesis through the ITGA9/VEGF-C pathway and promote lymphatic metastasis. Conclusions: Our study provided new insight into GBC pathogenesis that chronic bacterial infection and gallstones leading to the production of carcinogenic precursors and inflammatory cytokines promote lymphangiogenesis and lymph node metastasis of cancer cells through CACUL1/NRF2/ITGBL1/ ITGA9/VEGF-C pathway.

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supporting

confidence: 74%

Section: Cacul1 Upregulated the Expression Of Itgbl1 Through Nrf2mentioning

confidence: 97%

Abnormal Inflammatory Status Promotes Lymphatic Metastasis of Gallbladder Cancer Cells Through the CACUL1/NRF2/ITGBL1/ITGA9/VEGF-C Pathway

Kong¹,

Wang²,

Suo³

2021

Preprint

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“…How other candidates contributes to senescence will be our future interest. Cacul1 was found to down-regulate p53 transcriptional activity, regulation oxidative pressure and apoptosis (Kong et al, 2013;Kigoshi et al, 2015;Fukuda et al, 2017), which suggest Cacul1 may act as a suppress factor in cell aging process. Trdmt1 plays an important role in tRNA methylation to prevent tRNA cleavage into fragment, thus stabilize overall translation (Ghanbarian et al, 2016;Jeltsch et al, 2017).…”

Section: Discussionmentioning

confidence: 97%

mTORC1-Rps15 Axis Contributes to the Mechanisms Underlying Global Translation Reduction During Senescence of Mouse Embryonic Fibroblasts

et al. 2019

Front. Cell Dev. Biol.

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The reduction of protein translation is a common feature in senescent cells and aging organisms, yet the underlying mechanisms are not fully understood. Here we show that both global mRNA translation and mammalian/mechanistic target of rapamycin complex 1 (mTORC1) kinase activity are declined in a senescent model of mouse embryonic fibroblasts (MEFs). Furthermore, RNA-seq analyses from polysomal versus total mRNA fractions identify TOP-like mRNA of Rps15 whose translation is regulated by mTORC1 during MEF senescence. Overexpression of Rps15 delays MEF senescence, possibly through regulating ribosome maturation. Together, these findings indicate that the activation of mTORC1-Rps15 axis ameliorate senescence by regulating ribosome biogenesis, which may provide further insights into aging research.

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“…It has been suggested that CAC1 knockdown might lead to increased cellular stress response and p53 protein expression [17]. In another study, CAC1 was suggested as the positive regulator of Nrf2 in cell survival [12].…”

Section: Discussionmentioning

confidence: 99%

“…CDK2-associated cullin domain 1 (CAC1) is mapped to chromosome 10 in humans (10q35-36, Gene Bank accession number AY743663) [11], and is classified as a cullin domain-containing protein and a member of the cullin family of E3 ubiquitin ligases [12]. It has been shown that CAC1 promotes cell cycle progression and activates cyclin-dependent kinase 2 (CDK2) kinase activity via multiple extracellular signals, including growth factors, mitogens, deoxycholic acid (DCA), curcumin, and even chemotherapy drugs [13, 14].…”

Section: Introductionmentioning

confidence: 99%

CAC1 knockdown reverses drug resistance through the downregulation of P-gp and MRP-1 expression in colorectal cancer

Chen

Kong

et al. 2019

PLoS ONE

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CDK2-associated cullin domain 1 (CAC1) is as a novel cell cycle regulator widely expressed in colorectal cancer (CRC). However, its expression and function in drug resistant CRC cells remains elusive. Therefore, the present study aimed to assess the biochemical function and relevance of CAC1 in drug resistant CRC cells, and detect the potential mechanism. For this purpose, a total of 83 CRC cases were collected for the immunohistochemical analysis of CAC1 expression. Functional studies (stable transfection, flow cytometry, colony formation, and invasion and migration assays) were performed in SW480, LoVo and their corresponding 5-FU resistant cells. In addition, a nude mice xenograft model was established for further observation in vivo. In the present study, CAC1 protein expression was higher in CRC tissues than that in normal tissues (P<0.05). Furthermore, CAC1 protein expression was higher in SW480/5-FU cells than in SW480 cells. CAC1 knockdown arrested 5-FU resistant cells at the G1/S phase and increased the sensitivity of 5-FU resistant cells to 5-FU by inducing apoptosis. In addition, CAC1 reduced the invasive and migration ability of SW480/5-FU and LoVo/5-FU cells in vitro, and reduced their tumorigenicity and metastatic ability in vivo. Finally, CAC1 knockdown resulted in decreased P-glycoprotein and MRP-1 protein expression. Based on these results, it can be concluded that CAC1 plays an important role in the occurrence and promotion of drug resistance in CRC. Therefore, the knockdown of CAC1 may be considered as a new strategy for the development of CRC drug resistance treatments in the future.

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CACUL1/CAC1 Regulates the Antioxidant Response by Stabilizing Nrf2

Cited by 7 publications

References 58 publications

Abnormal Inflammatory Status Promotes Lymphatic Metastasis of Gallbladder Cancer Cells Through the CACUL1/NRF2/ITGBL1/ITGA9/VEGF-C Pathway

Abnormal Inflammatory Status Promotes Lymphatic Metastasis of Gallbladder Cancer Cells Through the CACUL1/NRF2/ITGBL1/ITGA9/VEGF-C Pathway

mTORC1-Rps15 Axis Contributes to the Mechanisms Underlying Global Translation Reduction During Senescence of Mouse Embryonic Fibroblasts

CAC1 knockdown reverses drug resistance through the downregulation of P-gp and MRP-1 expression in colorectal cancer

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