Reciprocal regulation of p21 and Chk1 controls the cyclin D1-RB pathway to mediate senescence onset after G2 arrest

Lossaint, Gerald; Horvat, Anđela; Gire, Véronique; Bačević, Katarina; Mrouj, Karim; Charrier‐Savournin, Fabienne; Georget, Virginie; Fisher, Daniel; Dulić, Vjekoslav

doi:10.1242/jcs.259114

Cited by 14 publications

(8 citation statements)

References 79 publications

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“…Furthermore, in cells released from growth arrest, RB is not inactivated by CDK4/6-mediated phosphorylation, but by hyperphosphorylation, which, upon the stimulation of growth-arrested cells, occurs coincidently with the onset of the S-phase and active CDK2 complexes [58,59]-the opposite conclusion to earlier work [60]. In cycling cells, RB phosphorylation and inactivation are maintained throughout the cell cycle, and long-term cell cycle arrest triggered by RB dephosphorylation can occur in G2 [61]. Analogously, new research suggests that even in budding yeast, acute nutrient deprivation can provoke growth arrest independently of the cell cycle stage [62].…”

Section: "G1" Cyclin-cdk Complexes May Control Growth Rather Than S-p...mentioning

confidence: 89%

Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models

Fisher

Krasińska

2022

Cells

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In eukaryotes, cyclin-dependent kinases (CDKs) are required for the onset of DNA replication and mitosis, and distinct CDK–cyclin complexes are activated sequentially throughout the cell cycle. It is widely thought that specific complexes are required to traverse a point of commitment to the cell cycle in G1, and to promote S-phase and mitosis, respectively. Thus, according to a popular model that has dominated the field for decades, the inherent specificity of distinct CDK–cyclin complexes for different substrates at each phase of the cell cycle generates the correct order and timing of events. However, the results from the knockouts of genes encoding cyclins and CDKs do not support this model. An alternative “quantitative” model, validated by much recent work, suggests that it is the overall level of CDK activity (with the opposing input of phosphatases) that determines the timing and order of S-phase and mitosis. We take this model further by suggesting that the subdivision of the cell cycle into discrete phases (G0, G1, S, G2, and M) is outdated and problematic. Instead, we revive the “continuum” model of the cell cycle and propose that a combination with the quantitative model better defines a conceptual framework for understanding cell cycle control.

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Section: "G1" Cyclin-cdk Complexes May Control Growth Rather Than S-p...mentioning

confidence: 89%

Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models

Fisher

Krasińska

2022

Cells

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“…For instance, cyclin-dependent kinase 3 ( CDK3 ) can phosphorylate a subunit of activating protein 1 (AP1) and promote the EMT process in CRC cells ( 27 ). Cyclin-dependent kinase inhibitor 1A ( CDKN1A ), also known as p21 , is a tumor suppressor ( 28 ). The suppression of CDKN1A in tumor cells mainly affects cell cycle progression, leading to uncontrolled cell proliferation ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cyclin-dependent kinase inhibitor 1A ( CDKN1A ), also known as p21 , is a tumor suppressor ( 28 ). The suppression of CDKN1A in tumor cells mainly affects cell cycle progression, leading to uncontrolled cell proliferation ( 28 ). However, the promoters of CDK3 and CDKN1A do not contain the SIX5 binding site, suggesting that they may not be the direct target genes of the EYA3-SIX5-p300 complex.…”

Section: Discussionmentioning

confidence: 99%

Both a hypoxia-inducible EYA3 and a histone acetyltransferase p300 function as coactivators of SIX5 to mediate tumorigenesis and cancer progression

Chao¹,

Liu²

2022

Ann Transl Med

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Background: The transcription partners of eyes absent homologs and sine oculis homeobox homologs (EYA-SIX) contribute to tumorigenesis and progression of multiple cancers through mediating the expression of oncogenes and tumor suppressors. This study aimed to determine the roles of individual EYA-SIX partners and their downstream targets in colorectal cancer (CRC).Methods: Immunoblot and real-time quantitative polymerase chain reaction (RT-qPCR) were used to measure protein and gene expression levels. Cell Counting Kit-8 (CCK-8) assay, colony formation, cell invasion assays, and a tumor xenograft model were chosen to investigate tumor cell growth.Immunoprecipitation, mass spectrometry, and co-immunoprecipitation (Co-IP) experiments were performed to determine the assembly of the SIX5-associated complex. Chromatin immunoprecipitation (ChIP) assay was used to evaluate the occupancy of SIX5-associated complex on its target gene promoters. Results:We discovered that the hypoxia-induced EYA3 coupled with SIX5 and a histone acetyltransferase p300 to assemble a complex in CRC biopsies. The EYA3-SIX5-p300 complex was required for the transactivation of epidermal growth factor receptor (EGFR), vascular endothelial growth factor D (VEGFD), and five matrix metallopeptidases (MMPs), including MMP3, MMP7, MMP8, MMP21, and MMP26. The results of ChIP revealed that the EYA3-SIX5-p300 complex specifically bound to the promoters of EGFR/ VEGFD/MMPs. Disruption of the assembly of EYA3-SIX5-p300 complex decreased the expression of EGFR/VEGFD/MMPs, inhibiting CRC cell growth. Administration of EYA3 inhibitor (benzarone) in mice harboring tumor xenografts significantly inhibited tumor growth. Conclusions:The hypoxia-dependent EYA3-SIX5-p300 complex is involved in the pathogenesis of CRC through mediating EGFR/VEGFD/MMPs and targeting this complex may represent a new therapeutic strategy for CRC treatment.

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“…Conversely, Chk1 depletion promotes senescence by inducing p21 binding to cyclin D1-and cyclin E1-CDK complexes and downregulating CDK6, whereas knockdown of the checkpoint kinase Chk2 enables RB phosphorylation and delays G2 exit. In conclusion, p21 and Chk2 oppose Chk1 to maintain RB activity, thus promoting the onset of senescence induced by DNA damage in G2 29 .…”

Section: Spontaneous Aging Along With 10 Gy Radiation Induced Senesce...mentioning

confidence: 91%

Impact of nicotinamide mononucleotide (NMN) and platelet rich fibrin (PRF) on senescence in spontaneously aging and irradiated human osteoblasts

Hakim

Gracht

Pries

et al. 2022

Preprint

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With the increasing human lifespan, bone aging and related pathologies increasingly contribute to the musculo-skelettal homeostasis, and senescence related osteoblasts disorders are supposed to play a key role in osteoporosis, osteonecrosis and bone remodeling diseases. Only limited studies have elucidated the histomorphological and molecular changes in senescent human osteoblasts (OBs) and their potential treatment.In the present study we investigated the cellular changes induced by spontaneous inherent as well as radiation-induced senescence in OBs and the impact of addition cultivation with nicotinamide mononucleotide (NMN) and platelet rich fibrin (PRF) on apoptosis, senescence-associated β-galactosidase staining and senescence related gene expression using RT2 Profiler PCR array. We found that OBs alteration through spontaneous inherent aging follows a different pathway than that of radiation-induced cellular senescence. Both NMN and PRF seem to provide a senescence and radioprotective effect on human OBs, albeit by different mechanisms. These results provide evidence on the potential clinical implication of systematic NMN administration and local PRF application to prevent age-related bone disturbance in elderly patients.

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Reciprocal regulation of p21 and Chk1 controls the cyclin D1-RB pathway to mediate senescence onset after G2 arrest

Cited by 14 publications

References 79 publications

Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models

Explaining Redundancy in CDK-Mediated Control of the Cell Cycle: Unifying the Continuum and Quantitative Models

Both a hypoxia-inducible EYA3 and a histone acetyltransferase p300 function as coactivators of SIX5 to mediate tumorigenesis and cancer progression

Impact of nicotinamide mononucleotide (NMN) and platelet rich fibrin (PRF) on senescence in spontaneously aging and irradiated human osteoblasts

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