Fission Yeast TORC2 Signaling Pathway Ensures Cell Proliferation under Glucose-Limited, Nitrogen-Replete Conditions

Target of rapamycin (TOR) kinases form two distinct complexes, TORC1 and TORC2, which are evolutionarily conserved among eukaryotes. These complexes control intracellular biochemical processes in response to changes in extracellular nutrient conditions. Previous studies using the fission yeast, Schizosaccharomyces pombe, showed that the TORC2 signaling pathway, which is essential for cell proliferation under glucose-limited conditions, ensures cell-surface localization of a high-affinity hexose transporter, Ght5, by downregulating its endocytosis. The TORC2 signaling pathway retains Ght5 on the cell surface, depending on the presence of nitrogen sources in medium. Ght5 is transported to vacuoles upon nitrogen starvation. In this review, we discuss the molecular mechanisms underlying this regulation to cope with nutritional stress, a response which may be conserved from yeasts to mammals.

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TORC2 inhibition of α-arrestin Aly3 effects cell surface persistence of S. pombe Ght5 glucose transporter in low-glucose

Journal of Cell Science ◽

10.1242/jcs.257485 ◽

2021 ◽

Author(s):

Yusuke Toyoda ◽

Saeko Soejima ◽

Fumie Masuda ◽

Shigeaki Saitoh

Keyword(s):

Cell Surface ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Gene Mutations ◽

Gene Encoding ◽

Glucose Depletion ◽

Hexose Transporters ◽

Surface Localization ◽

Cell Surface Localization ◽

Dependent Transport

In the fission yeast, Schizosaccharomyces pombe, the high-affinity hexose transporter, Ght5, must be transcriptionally upregulated and localized to the cell surface for cell division under limited glucose. While cell-surface localization of Ght5 depends on Target Of Rapamycin Complex 2 (TORC2), the molecular mechanisms by which TORC2 ensures proper localization of Ght5 remain unknown. We performed genetic screening for gene mutations that restore Ght5 localization on the cell surface in TORC2-deficient mutant cells, and identified a gene encoding an uncharacterized α-arrestin-like protein, Aly3/SPCC584.15c. α-arrestins are thought to recruit a ubiquitin ligase to membrane-associated proteins. Consistently, Ght5 is ubiquitinated in TORC2-deficient cells, and this ubiquitination is dependent on Aly3. TORC2 supposedly enables cell-surface localization of Ght5 by preventing Aly3-dependent ubiquitination and subsequent ubiquitination-dependent translocation of Ght5 to vacuoles. Surprisingly, nitrogen starvation, but not glucose depletion, triggers Aly3-dependent transport of Ght5 to vacuoles in S. pombe, unlike budding yeast hexose transporters, vacuolar transport of which is initiated upon changes in the hexose concentration. This study provides new insights into molecular mechanisms controlling subcellular localization of hexose transporters in response to extracellular stimuli.

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Cell surface localization of importin α1/KPNA2 affects cancer cell proliferation by regulating FGF1 signalling

Scientific Reports ◽

10.1038/srep21410 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 16

Author(s):

Kohji Yamada ◽

Yoichi Miyamoto ◽

Akira Tsujii ◽

Tetsuji Moriyama ◽

Yudai Ikuno ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Surface ◽

Cancer Cell ◽

Cancer Cell Proliferation ◽

Surface Localization ◽

Cell Surface Localization

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Evaluation of MACF1-regulatory non-coding RNA as a potential therapeutic target in Colorectal Cancer

QJM ◽

10.1093/qjmed/hcab088.011 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Rowaida Mohammed Reda M. M Aboushahba ◽

Fayda Ibrahim Abdel Motaleb ◽

Ahmed Abdel Aziz Abou-Zeid ◽

Enas Samir Nabil ◽

Dalia Abdel-Wahab Mohamed ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Wnt Signaling ◽

Cell Line ◽

Signaling Pathway ◽

Therapeutic Target ◽

Molecular Mechanisms ◽

Wnt Signaling Pathway ◽

Control Group ◽

Potential Therapeutic Target

ABSTRACT Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths world-wide. There is an increasing need for the identification of novel biomarkers/targets for early diagnosis and for the development of novel chemopreventive and therapeutic agents for CRC. Recently, MACF1 gene has emerged as a potential therapeutic target in cancer as it involved in processes critical for tumor cell proliferation, invasion and metastasis. It is suggested that MACF1 may function in cancers through Wnt signaling. MiR-34a is a well-known tumor suppressor miRNA.miR-34a targets MACF1 gene as a part of the wnt signaling pathway. In this study, 40 colonic tissues were collected from CRC patients (20) and control subjects (20). miR-34a-5p was assessed by real time PCR in all study groups. The results showed highly significant decrease (P < 0.01) in miR-34a relative expression in the CRC group (median RQ 0.13) when compared to the benign group (median RQ 5.3) and the healthy control group (median RQ 19.63). miR-34a mimic and inhibitor were transfected in CaCo-2 cell line and proliferation was assessed. The transfection of the cell line with miR-34a mimic decreased cell proliferation. Our study suggests that miR-34a-5p targets MACF1 gene as a part of the wnt signaling pathway leading to the involvement in the molecular mechanisms of CRC development and progression.

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Clinical significance of activated Wnt/β-catenin signaling in apoptosis inhibition of oral cancer

Open Life Sciences ◽

10.1515/biol-2021-0104 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1045-1052

Author(s):

Yufeng Wang ◽

Zheng Cao ◽

Fengjia Liu ◽

Yuejian Ou

Keyword(s):

Cell Proliferation ◽

Signaling Pathway ◽

Apoptotic Cell ◽

Cancer Cell Proliferation ◽

Rt Pcr ◽

Sirna Transfection ◽

Apoptosis Resistance ◽

Apoptosis Inhibition ◽

Anti Cancer ◽

Evolutionarily Conserved

Abstract Wnt/β‐catenin signaling is an evolutionarily conserved pathway and plays a crucial role in regulating cancer cell proliferation and tumorigenesis. However, the molecular mechanism behind the Wnt/β‐catenin signaling-mediated carcinogenesis and apoptosis resistance in oral squamous cell carcinoma is not well characterized so far. In the present study, we have investigated the effect of β‐catenin depletion of the perversely activated Wnt/β-catenin signaling pathway on apoptosis resistance and tumorigenesis of the human OSCC cell line SCC-55. RT-PCR and western blot analysis demonstrated that the Wnt/β-catenin signaling pathway and its downstream targets such as DKK1 and AXIN2 are aberrantly activated in SCC-55 cells. Furthermore, upon silencing (RNA interference) of β‐catenin in SCC-55, cells became more sensitive toward the chemotherapeutic drugs and thus resulted in apoptotic cell death. Meanwhile, flow cytometry analysis confirmed the enhanced apoptosis and activation of caspases in β‐catenin RNAi cells. Besides ensuing β-catenin–siRNA transfection, the cell proliferation and cancer colony generating efficiencies are significantly impeded compared to the non-transfected cells. Furthermore, the tumorigenicity was inhibited by the downregulation of OCT-4 in β‐catenin-silenced SCC-55 cells. Altogether, Wnt/β‐catenin signaling could potentially target anti-cancer drugs to induce apoptosis and achieve a better clinical outcome.

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A novel motif in the proximal C-terminus of Pannexin 1 regulates cell surface localization

Scientific Reports ◽

10.1038/s41598-019-46144-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Anna L. Epp ◽

Sarah N. Ebert ◽

Juan C. Sanchez-Arias ◽

Leigh E. Wicki-Stordeur ◽

Andrew K. J. Boyce ◽

...

Keyword(s):

Cell Surface ◽

Pannexin 1 ◽

C Terminus ◽

Surface Localization ◽

Cell Surface Localization

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miR-3188 Regulates Cell Proliferation, Apoptosis, and Migration in Breast Cancer by Targeting TUSC5 and Regulating the p38 MAPK Signaling Pathway

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504017x14953948675421 ◽

2018 ◽

Vol 26 (3) ◽

pp. 363-372 ◽

Cited By ~ 11

Author(s):

Xiaowen Chen ◽

Jianli Chen

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

P38 Mapk ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Luciferase Reporter ◽

And Migration ◽

Mcf 7

This study intended to investigate the effects of miR-3188 on breast cancer and to reveal the possible molecular mechanisms. miR-3188 was upregulated and TUSC5 was downregulated in breast cancer tissues and MCF-7 cells compared to normal tissue and MCF-10 cells. After MCF-7 cells were transfected with miR-3188 inhibitor, cell proliferation and migration were inhibited, whereas apoptosis was promoted. Luciferase reporter assay suggested that TUSC5 was a target gene of miR-3188. In addition, miR-3188 overexpression increased the p-p38 expression, while miR-3188 suppression decreased the p-p38 expression significantly. miR-3188 regulated breast cancer progression via the p38 MAPK signaling pathway. In conclusion, miR-3188 affects breast cancer cell proliferation, apoptosis, and migration by targeting TUSC5 and activating the p38 MAPK signaling pathway. miR-3188 may serve as a potential therapeutic agent for the treatment of breast cancer.

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