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P21, ccng1, foxo3b and fbxw7 contribute to p53-dependent cell-cycle arrest [PNP IR]

ABSTRACT: p53 is a transcription factor that plays a critical role in cancer prevention. However, the mechanisms by which p53 exerts its tumor-suppressive function is still unclear. While PUMA/BBC3 and NOXA/PMAIP1 are known to be important in p53-dependent apoptosis, and p21/CDKN1A is crucial for p53-dependent cell-cycle arrest, we demonstrate that zebrafish lacking puma, noxa, and p21 do not show a predisposition to cancer. This suggests that additional p53 transcriptional targets are sufficient for its tumor suppressive function. Contrary to the prevailing belief that p21 is the key regulator of p53-dependent cell-cycle arrest, we provide evidence that p53 can still induce cell-cycle arrest in the absence of p21, following DNA damage or loss of mdm2 (p53 activation in the absence of stress). This implies the involvement of other p53 transcriptional targets in mediating p53-dependent cell-cycle arrest. Since p53 tumor suppression is conserved across multiple vertebrate species, we conducted a cross-species comparative analysis of p53-dependent transcriptional profiles to identify a conserved set of 136 p53-upregulated transcripts. Our analysis stresses the importance of ortholog to paralog analysis across species, since in many cases the paralog but not ortholog in differing species is p53 dependent. Additionally, we performed a CRISPR/Cas9 G0 “crispant” screen in a genetic background lacking mdm2, puma, noxa, and p21 to identify key components involved in p53-dependent cell-cycle arrest. Our findings revealed that ccng1, fbxw7, and foxo3b play an important role in this process.

ORGANISM(S): Danio rerio

PROVIDER: GSE288660 | GEO | 2025/06/16

REPOSITORIES: GEO

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p21, ccng1, foxo3b and fbxw7 contribute to p53-dependent cell-cycle arrest [MPNP 18hpf]

Project description:p53 is a transcription factor that plays a critical role in cancer prevention. However, the mechanisms by which p53 exerts its tumor-suppressive function is still unclear. While PUMA/BBC3 and NOXA/PMAIP1 are known to be important in p53-dependent apoptosis, and p21/CDKN1A is crucial for p53-dependent cell-cycle arrest, we demonstrate that zebrafish lacking puma, noxa, and p21 do not show a predisposition to cancer. This suggests that additional p53 transcriptional targets are sufficient for its tumor suppressive function. Contrary to the prevailing belief that p21 is the key regulator of p53-dependent cell-cycle arrest, we provide evidence that p53 can still induce cell-cycle arrest in the absence of p21, following DNA damage or loss of mdm2 (p53 activation in the absence of stress). This implies the involvement of other p53 transcriptional targets in mediating p53-dependent cell-cycle arrest. Since p53 tumor suppression is conserved across multiple vertebrate species, we conducted a cross-species comparative analysis of p53-dependent transcriptional profiles to identify a conserved set of 136 p53-upregulated transcripts. Our analysis stresses the importance of ortholog to paralog analysis across species, since in many cases the paralog but not ortholog in differing species is p53 dependent. Additionally, we performed a CRISPR/Cas9 G0 “crispant” screen in a genetic background lacking mdm2, puma, noxa, and p21 to identify key components involved in p53-dependent cell-cycle arrest. Our findings revealed that ccng1, fbxw7, and foxo3b play an important role in this process.

2025-06-16 | GSE288667 | GEO

p21, ccng1, foxo3b and fbxw7 contribute to p53-dependent cell-cycle arrest [MPNP timecross]

2025-06-16 | GSE288666 | GEO

p21, ccng1, foxo3b and fbxw7 contribute to p53-dependent cell-cycle arrest [Mouse IR]

2025-06-16 | GSE288659 | GEO

Repurposing MDM2 Inhibitor RG7388 For TP53-Mutant NSCLC: A p53-Independent Pyroptotic Mechanism via ROS/p-p38/NOXA/Caspase-3/GSDME Axis

Project description:Non-small cell lung cancer (NSCLC) is highly malignant with limited treatment options due to the inherent tumoral heterogeneity and acquired resistance towards chemotherapy and immunotherapy. RG7388 was previously reported to have anticancer activity against TP53WT NSCLC which was designed as MDM2 inhibitor triggering p53/PUMA axis-dependent apoptosis. However, RG7388 exhibited p53-independent anticancer effect against TP53mutant NSCLC in our current research, the underlying mechanisms of which were still uncertain. Here, we reported that RG7388 specifically induced NOXA/Caspase-3 axis dependent apoptosis and gasdermin E (GSDME)-mediated secondary pyroptosis in TP53mutant NSCLC using in silico and multiple biological methods. Mechanically, we identified accumulated reactive oxygen species (ROS) served as the pivotal factor in NOXA upregulation and p38 MAPK pathway activation in RG7388 treated TP53mutant NSCLC by using two ROS scavengers N-acetylcysteine (NAC) and Ferrostatin-1 (Fer-1) respectively. Furthermore, pharmacologic inhibition of p38 MAPK signaling by SB203580 rescued RG7388 induced ROS-dependent NOXA accumulation and subsequent apoptosis and pyroptosis, thus suggesting a leading role of ROS/phosphorylated p38 MAPK (p-p38)/NOXA/Caspase-3 axis in RG7388 induced TP53mutant NSCLC cell death. Taken together, our work unraveled a novel mechanism of selective targeting of mutant p53 derived cancers via ROS/p-p38-mediated NOXA accumulation that could have potential therapeutic implications given the relative lack of direct mutant p53 targeting strategies in cancer. Moreover, A strong positive correlation between p-p38 and NOXA expression was confirmed by using an NSCLC tissue microarray and immunohistochemical (IHC) staining. Clinical data analysis suggested that the p-p38/NOXA axis could serve as a potential indicator for predicting overall survival (OS) in NSCLC patients.

2025-06-12 | GSE287938 | GEO

The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation

Project description:p53 executes its diverse functions via different transcriptional targets, but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify PURB, a dual DNA/RNA-binding protein, which acts as a transcriptional co-repressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers while its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and Mdm2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with lncRNA HOTAIR to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB/HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets indicates a number of promoters that may serve as a target for PURB-binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.

2025-04-24 | PXD042681 | Pride

Gene expression patterns induced by 5-Fluorouracil in breast cancer cell lines

Project description:We have compared the changes in cell cycle and cell death parameters induced by 2 different concentrations of 5-FU (IC50 and IC80) in the breast adenocarcinoma cell line MCF7. G1/S cell cycle arrest was associated with both concentrations, whereas cell death was mainly induced after IC80 5-FU. These changes were correlated with gene expression assessed by cDNA microarray analysis. Main findings included an overexpression of p53 target genes involved in cell cycle and apoptosis (CDKN1A/p21, TP53INP, TNFRSF6/FAS and BBC3/PUMA), and significant repression of Myc. High dose 5-FU also induced a higher regulation of the mitochondrial death genes APAF1, BAK1 and BCL2, and induction of genes of the ID family. Time and dose-dependent changes in gene expression, induced by 5-Fluorouracil, in breast carcinoma cell lines MCF7, and MDA-MB-435.

2010-07-01 | E-GEOD-2584 | biostudies-arrayexpress

Analysis of gene expression in p53-null cell types following deletion of Mdm2

Project description:RNA-sequencing was performed to gain insight into the mechanism responsible for the apoptosis and cell cycle arrest induced by loss of Mdm2 in p53-null cells. Following CreERT2-mediated deletion of Mdm2 in three p53-null cell types (T cell lymphoma, sarcoma, and fibroblasts), RNA-sequencing was performed. This high-throughput data revealed Mdm2 deletion in p53-null cells upregulated p53/p73 transcriptional target genes known to induce apoptosis and cell cycle arrest.

2017-09-06 | GSE98705 | GEO

The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation [RNA-Seq]

Project description:p53 executes its diverse functions via different transcriptional targets, but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify PURB, a dual DNA/RNA-binding protein, that acts as a transcriptional co-repressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers while its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and Mdm2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with lncRNA HOTAIR to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB/HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets indicates a number of promoters that may serve as a target for PURB-binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.

2025-04-24 | GSE295588 | GEO

The PURB-HOTAIR complex regulates p53-dependent promoter-specific transcriptional activation [CLIP-Seq]

Project description:p53 executes its diverse functions via different transcriptional targets, but the precise mechanism of promoter-specific regulation by p53 remains largely unknown. Through biochemical purification, we identify PURB, a dual DNA/RNA-binding protein, that acts as a transcriptional co-repressor for p53 in a manner dependent on p53 acetylation status. PURB is overexpressed in human cancers while its knockdown induces p53-dependent activation of p21 but has no effect on other major promoters such as PUMA and Mdm2. In contrast to other p53 corepressors, PURB can recognize a unique DNA element at the p21 promoter, with the loss of this element not affecting p53-mediated transactivation but abrogating the ability of p53 to recruit PURB to the p21 promoter for repression. Mechanistically, PURB requires its sequence-specific binding with lncRNA HOTAIR to exert its repressive role. In turn, HOTAIR interacts directly with EZH2 and, bridged by the PURB/HOTAIR complex, p53 can recruit the EZH2 histone methyltransferase to target promoters for transcriptional repression. Further analysis of p53 targets indicates a number of promoters that may serve as a target for PURB-binding, suggesting that this mechanism of PURB-dependent promoter-specific regulation may not be limited to p21. These data establish a mode of LncRNA-mediated regulation of p53 transcription in a sequence-specific manner and reveal a previously unanticipated mechanism for acetylation-mediated promoter-specific regulation through a cis-regulatory element recognized by the PURB-HOTAIR complex.

2025-04-25 | GSE295618 | GEO

CDK4/6 inhibitor-mediated cell overgrowth triggers an osmotic stress response

Project description:Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence and permanent cell cycle arrest. The mechanism by which overgrowth primes cells to withdraw from the cell cycle remains unknown. We investigate this here using CDK4/6 inhibitors that arrest cell cycle progression during G0/G1 and are used in the clinic to treat ER+/HER2- metastatic breast cancer. We demonstrate that CDK4/6 inhibition promotes cellular overgrowth during G0/G1, causing p38MAPK-p53-p21-dependent cell cycle withdrawal. We find that cell cycle withdrawal is triggered by two waves of p21 induction. First, overgrowth during a long-term G0/G1 arrest induces an osmotic stress response. This stress response produces the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape long term G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. We propose a model whereby both waves of p21 induction contribute to promote permanent cell cycle arrest. This model could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

2023-11-27 | PXD036519 | Pride

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