Cell cycle control in cancer

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 23(1), С. 74 - 88

Опубликована: Сен. 10, 2021

Язык: Английский

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Integrating Old and New Paradigms of G1/S Control

Molecular Cell, Год журнала: 2020, Номер 80(2), С. 183 - 192

Опубликована: Сен. 17, 2020

Язык: Английский

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A unified model for the G1/S cell cycle transition

Nucleic Acids Research, Год журнала: 2020, Номер 48(22), С. 12483 - 12501

Опубликована: Окт. 14, 2020

Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited causes replication stress, DNA damage oncogenesis, highlighting the need strict regulation. Recent paradigm shifts conflicting reports demonstrate requirement a discussion of G1/S transition literature. Here, we review recent studies, propose unified model decision. In this model, competition between mitogen signalling over course mother cell cycle constitutes predominant control mechanism daughter cells. Mitogens have distinct sensing periods, giving rise to three Commitment Points (CP1-3). mitogen-independent in G1 phase, but remains sensitive damage, such as single strand breaks, most frequently-occurring lesions that uniquely threaten replication. To CP1-3, dedicated hubs integrate antagonistic mitogenic signals, regulating stoichiometric cyclin: CDK inhibitor ratio ultrasensitive CDK4/6 CDK2. This combines findings decades study, provides an updated foundation research.

Язык: Английский

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CRL4AMBRA1 is a master regulator of D-type cyclins

Nature, Год журнала: 2021, Номер 592(7856), С. 789 - 793

Опубликована: Апрель 14, 2021

Язык: Английский

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Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity

Cell, Год журнала: 2023, Номер 186(12), С. 2628 - 2643.e21

Опубликована: Июнь 1, 2023

Язык: Английский

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The ribotoxic stress response drives UV-mediated cell death

Cell, Год журнала: 2024, Номер 187(14), С. 3652 - 3670.e40

Опубликована: Июнь 5, 2024

While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also RNA, triggering transcriptome-wide ribosomal collisions and a ribotoxic stress (RSR). However, relative contributions, timing, regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, biochemical approaches to create chronological atlas signaling events activated cells responding UV damage. We discover that UV-induced apoptosis mediated by RSR kinase ZAK not through DDR. identify two negative-feedback modules regulate ZAK-mediated apoptosis: (1) GCN2 activation limits attenuates (2) activity leads phosphodegron autophosphorylation its subsequent degradation. These tune ZAK's collision levels establish regimes homeostasis, tolerance, death, revealing key role as cellular sentinel for nucleic acid

Язык: Английский

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Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells

Cell Systems, Год журнала: 2020, Номер 11(5), С. 478 - 494.e9

Опубликована: Окт. 27, 2020

Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth tumors but often leads to emergence slowly dividing persister cells, which constitute a reservoir for selection drug-resistant clones. In BRAFV600E melanomas, RAF and MEK inhibitors efficiently block signaling, cells emerge. Here, we show that escape drug-induced cell-cycle arrest via brief, sporadic ERK pulses generated by transmembrane receptors factors operating an autocrine/paracrine manner. Quantitative proteomics computational modeling pulsing is enabled rewiring mitogen-activated protein kinase (MAPK) signaling: from monomer-driven configuration drug sensitive receptor-driven involves Ras-GTP dimers resistant inhibitors. Altogether, this work shows pulsatile MAPK activation microenvironment generates persistent population melanoma rewires signaling sustain non-genetic resistance.

Язык: Английский

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Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1

Molecular Cell, Год журнала: 2019, Номер 76(4), С. 562 - 573.e4

Опубликована: Сен. 19, 2019

Язык: Английский

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CDK4/6 initiates Rb inactivation and CDK2 activity coordinates cell-cycle commitment and G1/S transition

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Окт. 7, 2022

Abstract External signaling controls cell-cycle entry until cells irreversibly commit to the cell cycle ensure faithful DNA replication. This process is tightly regulated by cyclin-dependent kinases (CDKs) and retinoblastoma protein (Rb). Here, using live-cell sensors for CDK4/6 CDK2 activities, we propose that initiates Rb inactivation activation, which coordinates timing of commitment sequential G1/S transition. Our data show activation induces thereby E2F driving a gradual increase in activity. We found rapid inhibition can reverse activity reaches high levels. suggests required initiate CDK2-Rb positive feedback CDK4/6-indpendent progression. Since also facilitates initiation replication, coupled with experiments, acutely increased cyclin E1 overexpression, indicate before triggering Together, our suggest inactivates begin necessary sufficient generate bistable switch phosphorylation These findings highlight how subsequently

Язык: Английский

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A novel method for generating glutamatergic SH-SY5Y neuron-like cells utilizing B-27 supplement

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Окт. 20, 2022

The human SH-SY5Y neuroblastoma cell line is widely used in neuroscience research as a neuronal model. Following differentiation to neuron-like state, cells become more morphologically similar neurons and form functional synapses. Previous studies have managed differentiate towards cholinergic, dopaminergic adrenergic fates. However, their application disease modeling remains limited other subtypes (e.g., glutamatergic, GABAergic) are also implicated neurological disorders, no current protocols exist generate these of differentiated cells. Our study aimed evaluate the use xeno-free version B-27, supplement commonly culture, for maintenance differentiation. To proliferative capacity cultured we performed growth curve analyses, immunocytochemical staining Ki-67 qRT-PCR track changes cycle progression. FBS or under serum-starved conditions were controls. We observed that show reduced proliferation rates accompanied by decreased CDK6 CDK1 expression following 4-day exposure suggesting B-27 induces quiescent state Importantly, this rate was not due increased apoptosis. As exit associated with differentiation, next sought determine fate B-27. B-27-cultured morphology, adopting pyramidal shapes extending neurites, upregulation markers ( GAP43 , TUBB3 SYP ). glutamatergic GLUL GLS These findings suggest may be non-toxic inducer demonstrates novel way using obtain populations dysregulated signaling variety neuropsychiatric neurodegenerative capability creates endless opportunities. ease culture allows researchers large-scale cultures high-throughput pharmacological toxicity studies. Also compatible growing popularity animal-component-free studies, B-27/SH-SY5Y system will valuable tool boost translational potential preliminary requiring origin.

Язык: Английский

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