TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells

Yamada, Chihiro; Morooka, Aya; Miyazaki, Syuji; Nagai, Masayoshi; Mase, Satoru; Iemura, Kenji; Tasnin, Most Naoshia; Takuma, Tsuneyuki; Nakamura, Shotaro; Morshed, Shamsul; Koike, Nobuyuki; Mostofa, Md. Golam; Rahman, Muhammad Arifur; Sharmin, Tasnuva; Katsuta, Haruko; Ohara, Kotaro; Tanaka, Kozo; Ushimaru, Takashi

doi:10.1016/j.isci.2021.103675

Cited by 4 publications

(3 citation statements)

References 108 publications

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“…Therefore, anaphase cells could potentially disable the mechanism responsible for coordinating the progression of the cell cycle and cellular growth. It has been described that the inactivation of TORC1 increases mitotic slippage after prolonged metaphase block [157], although we have shown that the downregulation of TORC1 in anaphase-arrested cells is unable to promote mitotic exit [156]. Interestingly, TORC1 is inactivated during mitosis in human cells too [158], which might indicate that TORC1 activity during the cell cycle is regulated in a similar way in eukaryotes.…”

Section: Torc1 Regulates Mitosis Progressionmentioning

confidence: 48%

TOR Complex 1: Orchestrating Nutrient Signaling and Cell Cycle Progression

Foltman,

Sanchez-Diaz

2023

IJMS

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The highly conserved TOR signaling pathway is crucial for coordinating cellular growth with the cell cycle machinery in eukaryotes. One of the two TOR complexes in budding yeast, TORC1, integrates environmental cues and promotes cell growth. While cells grow, they need to copy their chromosomes, segregate them in mitosis, divide all their components during cytokinesis, and finally physically separate mother and daughter cells to start a new cell cycle apart from each other. To maintain cell size homeostasis and chromosome stability, it is crucial that mechanisms that control growth are connected and coordinated with the cell cycle. Successive periods of high and low TORC1 activity would participate in the adequate cell cycle progression. Here, we review the known molecular mechanisms through which TORC1 regulates the cell cycle in the budding yeast Saccharomyces cerevisiae that have been extensively used as a model organism to understand the role of its mammalian ortholog, mTORC1.

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Section: Torc1 Regulates Mitosis Progressionmentioning

confidence: 48%

TOR Complex 1: Orchestrating Nutrient Signaling and Cell Cycle Progression

Foltman,

Sanchez-Diaz

2023

IJMS

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“…Studies have shown that the inhibition of TORC1 kinase can lead to MS in both budding yeast and human cells, ultimately resulting in chromosomal instability. During MS in yeast, several changes occur, including the activation of phosphatase Cdc14, the disintegration of the nucleolar protein Net1, and the degradation of the APC/C-Cdh1-dependent enzyme inhibitor protein and cyclin B during the mid-stage ( Yamada et al, 2022 ).…”

Section: Polyploid Giant Cells In Tumormentioning

confidence: 99%

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

Liu,

Wang,

2024

Front. Cell Dev. Biol.

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Polyploid giant cancer cells (PGCCs) are characterized by the presence of either a single enlarged nucleus or multiple nuclei and are closely associated with tumor progression and treatment resistance. These cells contribute significantly to cellular heterogeneity and can arise from various stressors, including radiation, chemotherapy, hypoxia, and environmental factors. The formation of PGCCs can occur through mechanisms such as endoreplication, cell fusion, cytokinesis failure, mitotic slippage, or cell cannibalism. Notably, PGCCs exhibit traits similar to cancer stem cells (CSCs) and generate highly invasive progeny through asymmetric division. The presence of PGCCs and their progeny is pivotal in conferring resistance to chemotherapy and radiation, as well as facilitating tumor recurrence and metastasis. This review provides a comprehensive analysis of the origins, potential formation mechanisms, stressors, unique characteristics, and regulatory pathways of PGCCs, alongside therapeutic strategies targeting these cells. The objective is to enhance the understanding of PGCC initiation and progression, offering novel insights into tumor biology.

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“…checkpoint proteins regulating DNA repair and mitosis) that have a direct link to CIN (Figure 1). Other miRNAs targeting important structural components such as the cohesin complex (involved in sister chromatid cohesion and the DNA damage response) (reviewed in (Kuru-Schors, Haemmerle et al 2021, Yamada, Morooka et al 2022, could also promote CIN although the direct causal relationship requires further study. miR-22 directly bound and repressed the levels of MDC1 in three different cell lines (HEK293T, HeLa, U2OS) (Lee, Park et al 2015).…”

Section: Micrornas Implicated In Cinmentioning

confidence: 99%

The Role of Non-Coding RNAs in Chromosomal Instability in Cancer

Mohapatra

Winkle

Ton

et al. 2022

J Pharmacol Exp Ther

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Chromosomal instability (CIN) is characterized by an increased frequency of changes in chromosome structure or number and is regarded as a hallmark of cancer. CIN plays a prevalent role in tumorigenesis and cancer progression by assisting the cancer cells' phenotypic adaptation to stress, which has been tightly linked to therapy resistance and metastasis. Both, CIN-inducing and CIN-repressing agents are being clinically tested for the treatment of cancer to increase CIN levels to unsustainable levels leading to cell death, or to decrease CIN levels to limit the development of drug resistance, respectively. Noncoding RNAs (ncRNAs) including micro RNAs (miRNAs) and long noncoding RNAs (lncRNAs) have been fundamentally implicated in CIN. The miR-22, miR-26a, miR-28, miR-186 target important checkpoint proteins involved in mediating chromosomal stability and their expression modulation has been directly related to CIN occurrence. LncRNAs derived from telomeric, centrosomal and enhancer regions play an important role in mediating genome stability, while specific lncRNA transcripts including Ginir, GUARDIN, CCAT2, PCAT2, and NORAD have been shown to act within CINassociated pathways. In this review, we discuss how these ncRNAs either maintain or disrupt the stability of chromosomes and how these mechanisms could be exploited for novel therapeutic approaches targeting CIN in cancer patients.

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TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells

Cited by 4 publications

References 108 publications

TOR Complex 1: Orchestrating Nutrient Signaling and Cell Cycle Progression

TOR Complex 1: Orchestrating Nutrient Signaling and Cell Cycle Progression

Polyploid giant cancer cells: origin, possible pathways of formation, characteristics, and mechanisms of regulation

The Role of Non-Coding RNAs in Chromosomal Instability in Cancer

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