scholarly journals p53 pro-apoptotic activity is regulated by the G2/M promoting factor Cdk1 in response to DNA damage

2021 ◽  
Author(s):  
Mireya Ruiz-Losada ◽  
Raul González ◽  
Ana Peropadre ◽  
Antonio Baonza ◽  
Carlos Estella
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Genotoxic Stress ◽  
Suppressor Gene ◽  
Cell Fate Decisions ◽  
Apoptotic Activity ◽  
Induced Apoptosis

SummaryExposure to genotoxic stress promotes cell-cycle arrest and DNA repair or apoptosis. These “life” or “death” cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, how p53 activity is precisely regulated is essential to maintain tissue homeostasis and to prevent cancer development. Here we demonstrate that Drosophila p53 pro-apoptotic activity is regulated by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation induced apoptosis. We show that the p53 protein is not able to bind to and to activate the expression of the pro-apoptotic genes in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 pro-apoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 pro-apoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

scholarly journals Coordination between cell proliferation and apoptosis after DNA damage in Drosophila

2021 ◽  
Author(s):  
Mireya Ruiz-Losada ◽  
Raul González ◽  
Ana Peropadre ◽  
Alejandro Gil-Gálvez ◽  
Juan J. Tena ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Genotoxic Stress ◽  
Regulatory Elements ◽  
Suppressor Gene ◽  
Cycle Progression ◽  
Cell Fate Decisions ◽  
Induced Apoptosis

AbstractExposure to genotoxic stress promotes cell cycle arrest and DNA repair or apoptosis. These “life” or “death” cell fate decisions often rely on the activity of the tumor suppressor gene p53. Therefore, the precise regulation of p53 is essential to maintain tissue homeostasis and to prevent cancer development. However, how cell cycle progression has an impact on p53 cell fate decision-making is mostly unknown. In this work, we demonstrate that Drosophila p53 proapoptotic activity can be impacted by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation-induced apoptosis. We show that p53 binding to the regulatory elements of the proapoptotic genes and its ability to activate their expression is compromised in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 proapoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 proapoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.

scholarly journals Regulation of p53 by Hypoxia: Dissociation of Transcriptional Repression and Apoptosis from p53-Dependent Transactivation

2001 ◽  
Vol 21 (4) ◽  
pp. 1297-1310 ◽  
Author(s):  
Constantinos Koumenis ◽  
Rodolfo Alarcon ◽  
Ester Hammond ◽  
Patrick Sutphin ◽  
William Hoffman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Target Genes ◽  
P53 Protein ◽  
Genotoxic Stress ◽  
Protein Accumulation ◽  
Dependent Cell ◽  
Apoptotic Activity ◽  
Induced Apoptosis

ABSTRACT Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.

scholarly journals TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation

2017 ◽  
Vol 292 (8) ◽  
pp. 3201-3212 ◽  
Author(s):  
Ryo Maeda ◽  
Hiroyuki Tamashiro ◽  
Kazunori Takano ◽  
Hiro Takahashi ◽  
Hidefumi Suzuki ◽  
...  
Keyword(s):  
Cell Fate ◽  
Nuclear Export ◽  
Cellular Response ◽  
P53 Protein ◽  
Genotoxic Stress ◽  
Negative Control ◽  
Cell Fate Decisions ◽  
Single Cell Imaging ◽  
P53 Activation ◽  
Induced Apoptosis

Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions.

scholarly journals Quantifying E2F1 protein dynamics in single cells

2019 ◽  
Author(s):  
Bernard Mathey-Prevot ◽  
Bao-Tran Parker ◽  
Carolyn Im ◽  
Cierra Hong ◽  
Peng Dong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Fusion Protein ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Single Cells ◽  
Protein A ◽  
Genotoxic Stress ◽  
Reporter Protein ◽  
Cell Fate Decisions ◽  
Steady State Levels

AbstractThe Rb/E2F pathway plays a central role in regulating cell-fate decisions and cell-cycle progression. The E2F1 protein, a major effector of the pathway, is regulated via a combination of transcriptional, translational and posttranslational constraints. Elucidating the regulation and impact of the Rb/E2F pathway requires direct measurement of E2F1 dynamics in single cells. To this end, we have engineered fluorescent E2F1 protein reporters to enable live detection and quantification in single cells. The reporter constructs expressed an E2F1-Venus fusion protein under the regulation of the mouse or human E2F1 promoter and contained or excluded the 3’UTR of the E2F1 gene, a sequence that contains miRNA regulatory regions that modulate expression of the protein. Expression of the reporter protein was highly dynamic during the cell cycle: there was no or little fluorescent signal in G0, but levels steadily increased during late G1 and peaked during mid to late S phase before returning to baseline before the onset of mitosis. The absence of the E2F1 3’UTR in the constructs led to considerably higher steady-state levels of the fusion protein, which although normally regulated, exhibited a slightly less complex dynamic profile during the cell cycle or genotoxic stress. Lastly, the presence or absence of Rb failed to impact in substantial ways the overall detection and levels of the reporters.

scholarly journals Cellular responses to a prolonged delay in mitosis are determined by a DNA damage response controlled by Bcl-2 family proteins

Open Biology ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 140156 ◽  
Author(s):  
Didier J. Colin ◽  
Karolina O. Hain ◽  
Lindsey A. Allan ◽  
Paul R. Clarke
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinases ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Anti Cancer ◽  
Damage Response ◽  
Microtubule Poisons

Anti-cancer drugs that disrupt mitosis inhibit cell proliferation and induce apoptosis, although the mechanisms of these responses are poorly understood. Here, we characterize a mitotic stress response that determines cell fate in response to microtubule poisons. We show that mitotic arrest induced by these drugs produces a temporally controlled DNA damage response (DDR) characterized by the caspase-dependent formation of γH2AX foci in non-apoptotic cells. Following exit from a delayed mitosis, this initial response results in activation of DDR protein kinases, phosphorylation of the tumour suppressor p53 and a delay in subsequent cell cycle progression. We show that this response is controlled by Mcl-1, a regulator of caspase activation that becomes degraded during mitotic arrest. Chemical inhibition of Mcl-1 and the related proteins Bcl-2 and Bcl-x L by a BH3 mimetic enhances the mitotic DDR, promotes p53 activation and inhibits subsequent cell cycle progression. We also show that inhibitors of DDR protein kinases as well as BH3 mimetics promote apoptosis synergistically with taxol (paclitaxel) in a variety of cancer cell lines. Our work demonstrates the role of mitotic DNA damage responses in determining cell fate in response to microtubule poisons and BH3 mimetics, providing a rationale for anti-cancer combination chemotherapies.

scholarly journals An Evolving Role for the Long Non-Coding RNA H19 in Aging and Senescence

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 563-563
Author(s):  
Christian Sell ◽  
Manali Potnis
Keyword(s):  
Cell Cycle ◽  
Somatic Cell ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Adult Stem Cells ◽  
Somatic Cells ◽  
Gene Transcript ◽  
Cell Fate Decisions ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract The long non-coding RNA (lncRNA) H19 is a maternally imprinted gene transcript that, in conjunction with the neighboring Igf2 gene, is critical in controlling embryonic growth. Loss of H19 results in fetal overgrowth associated with Beckwith Weidemann syndrome, while elevated H19 occurs in human cancers. In the adult, H19 functions in cancer cells where it promotes migration and is correlated with poor prognosis, and in adult stem cells where it is a key regulator of cell fate decisions during differentiation. While the function of H19 in primary somatic cells has not been defined, a reduction in the abundance of H19 has been reported during senescence in endothelial cells. Given the critical importance of H19 in cell fate decisions, it is likely that understanding the precise function of H19 in somatic cells in general and why reduced levels occur with cellular senescence will provide novel insights into both somatic cell maintenance and the senescence program. Towards this end, we examined the role of H19 in somatic cell growth using cardiac interstitial fibroblasts. Our results indicate that H19 is not only vital for somatic cell proliferation and survival, but that depletion of H19 leads to cell cycle arrest and the formation of abnormal nuclei resulting in senescent cells. We are defining both the upstream regulators of H19 and the downstream mediators of senescence following H19 depletion. Overall, these results indicate an essential role for H19 in cell cycle progression, chromatin structure, and possibly proper mitotic division.

scholarly journals Let-7 regulates cell cycle dynamics in the developing cerebral cortex and retina

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Corinne L. A. Fairchild ◽  
Simranjeet K. Cheema ◽  
Joanna Wong ◽  
Keiko Hino ◽  
Sergi Simó ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Developmental Time ◽  
Neural Progenitors ◽  
Cycle Progression ◽  
Cell Fate Decisions ◽  
Cell Cycle Dynamics

Abstract In the neural progenitors of the developing central nervous system (CNS), cell proliferation is tightly controlled and coordinated with cell fate decisions. Progenitors divide rapidly during early development and their cell cycle lengthens progressively as development advances to eventually give rise to a tissue of the correct size and cellular composition. However, our understanding of the molecules linking cell cycle progression to developmental time is incomplete. Here, we show that the microRNA (miRNA) let-7 accumulates in neural progenitors over time throughout the developing CNS. Intriguingly, we find that the level and activity of let-7 oscillate as neural progenitors progress through the cell cycle by in situ hybridization and fluorescent miRNA sensor analyses. We also show that let-7 mediates cell cycle dynamics: increasing the level of let-7 promotes cell cycle exit and lengthens the S/G2 phase of the cell cycle, while let-7 knock down shortens the cell cycle in neural progenitors. Together, our findings suggest that let-7 may link cell proliferation to developmental time and regulate the progressive cell cycle lengthening that occurs during development.

scholarly journals The DNA Damage-Induced Cell Cycle Checkpoints

2000 ◽  
Vol 2 (4) ◽  
pp. 237-243
Author(s):  
Piotr Widlak
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
P53 Protein ◽  
Critical Role ◽  
Cell Cycle Checkpoints ◽  
Signal Transduction Pathways ◽  
Cycle Progression

The proliferation of eukaryotic cells is driven by a process called the cell cycle. Proper regulation of this process, leading to orderly execution of sequential steps within the cycle, ensures normal development and homeostasis of the organism. On the other hand, perturbations of the cell cycle are frequently attributed to cancer cells. Mechanisms that ensure the order and fidelity of events in the cell cycle are called checkpoints. The checkpoints induced by damaged DNA delay the cell cycle progression, providing more time for repair of lesion before DNA replication and segregation. The DNA damage-induced checkpoints can be recognized as signal transduction pathways that communicate information between DNA lesion and components of the cell cycle. Proteins involved in the cell cycle, as well as components of the signal transduction pathways communicating with the cell cycle, are frequently products of oncogenes and tumor suppressor genes. Malfunction of these genes plays a critical role in the development of human cancers. The key component in the checkpoint machinery is tumor suppressor gene p53, involved in either regulation of the cell cycle progression (e.g. Gl arrest of cells treated with DNA damaging factor) or activation of programmed cell death (apoptosis). It is postulated that p53 protein is activated by DNA damage detectors. One of the candidates for this role is DNA-dependent protein kinase (DNA-PK) which recognizes DNA strand breaks and phosphorylates p53 protein.

Sign in / Sign up

Export Citation Format

Share Document