Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

P16INK4a mediated supperssion of telomerase in normal and malignant human breast cells

ABSTRACT: The cyclin-dependent kinase inhibitor p16INK4a (CDKN2A) is an important tumor-suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular senescence. Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression. We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells. Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes. Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal.

ORGANISM(S): Homo sapiens

PROVIDER: GSE14436 | GEO | 2009/12/01

SECONDARY ACCESSION(S): PRJNA111771

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

P16INK4a mediated supperssion of telomerase in normal and malignant human breast cells

Project description:The cyclin-dependent kinase inhibitor p16INK4a (CDKN2A) is an important tumor-suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular senescence. Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression. We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells. Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes. Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal. 27 samples were analyzed to study three histone modifications (H3K4me3, H3K9me3, H3K27me3) in three different cell lines. Each combination of histone modification and cell line had three biological replicates (A,B,C).

2010-05-19 | E-GEOD-14436 | biostudies-arrayexpress

Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (2)

Project description:In this study we examine the outcomes of p16INK4a activation in the adult epidermis. We found that prolonged expression of p16INK4a induces epidermal hyperplasia and dysplasia. We also found that continued p16INK4a expression increased the number of epidermal papillomas that developed after carcinogen treatment. Profling of p16INK4a- expressing cells showed elevated levels of Wnt-pathway ligands and targets, and pharmacologic or genetic Wnt inhibition suppressed p16-induced hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16-expressing cells are typically found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that in addition to its cell-autonomous role in blocking cell proliferation, p16 can induce hyperplasia through paracrine stimulation, suggesting that its activity contributes to the formation of early premalignant epidermal lesions.

2020-04-06 | GSE146978 | GEO

Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation (1)

2020-04-06 | GSE121728 | GEO

Linking immortalization to direct conversion of human fibroblasts to neurons

Project description:Direct conversion from fibroblasts to neurons is a potential cell replacement therapy for neurological disorders, and a variety of combinations of transcription factors have been tried. We notice that the efficiency of conversion from aging fibroblasts was much lower than in early stage cells, which is consistent with the notion that cellular senescence impairs conversion of fibroblasts to neurons. Here, we found that the transient knockdown of the p16Ink4a/p19Arf locus was sufficient to convert human fibroblasts to neurons. Futhermore, expression of hTERT alone, another mechanism behind immortalization, also induced neuron conversion. Our results show that the acquisition of immortality is a crucial step for the conversion of human fibroblasts into induced neurons. Transient knockdown of p16/p19 or p53 expression or exogenous overexpression of hTERT can induce primary fibroblasts to immortality. In the following, treated cells were cultured in neuron-induction medium. We can observe the morphology change and detect the neuronal markers. Also, some of the induced neurons could generate action potentials and neurotransmitter-induced currents in optimal conditions.

2012-12-28 | E-GEOD-43175 | biostudies-arrayexpress

Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [10X scRNA-seq]

Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs, at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared two p16-3MR+GCV to two WT+GCV control GBMs that were harvested 7 days after the last GCV injection. p16Ink4a Hi senescent cells were a subset of malignant cells, mostly grouped in the astrocyte cluster and to a lesser extend in the NP-like cluster. We also found that p16Ink4a Hi senescent cells deletion modifies the cell state of malignant cells and modulates the tumor microenvironment. This study allowed us to define a GBM senescence signature.

2022-12-15 | GSE168038 | GEO

Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [bulk RNA-seq]

Project description:GBM mouse model: The goal of this study is to compare the transcriptomic landscape at the endpoint of GBMs upon senescent cells deletion. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) upon ganciclovir (GCV) injection. We compared p16-3MR+GCV GBMs to two control conditions, either WT+GCV or p16-3MR+GCV. We showed a slight decreased of p16Ink4a transcripts in p16-3MR+GCV compared to WT+GCV GBMs and GSEA demonstrated significant down-regulation of senescence pathways in p16-3MR+GCV GBMs compared to control GBMs. GBM-derived organoids: We used a mouse GBM-derived organoids model to further explore the function of Nrf2, that we identified as one potential trigger of the pro-tumoral action of p16Ink4a Hi malignant cells. We compared GBM-derived organoids treated with the senolytic ABT263 (Navitoclax; inhibitor of the anti-apoptotic proteins Blcl2 and BCL-xL) or vehicle (vhc) after 14 days in culture. We validated ABT263 efficacy via the significant downregulation of the expression of p16Ink4a, p15Ink4b and p21Cip1 senescent markers. We further identified upon senolytic treatment, downregulated genes encoding for SASP. Importantly, GSEA revealed a significant downregulation of Nrf2 pathway upon senolytic treatment.

2022-12-15 | GSE168037 | GEO

Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A

Project description:p16INK4A inhibits the CDK4/6 kinases and is therefore an important cell cycle regulator. Accumulation of p16INK4A in response to oncogenic transformation leads to cellular senescence and it is therefore frequently lost in cancer. p16INK4A is also known to accumulate under conditions of cellular oxidative stress and therefore could potentially be regulated by redox signaling, which is a form of signal transduction that is mediated by the reversible oxidation of cysteine-thiol side chains in proteins. We found that oxidation of the single cysteine residue in p16INK4A in human cells occurs under relatively mild oxidizing conditions and that this leads to disulfide dependent dimerization. p16INK4A is a well-characterized all alpha-helical protein, but we find that upon cysteine-dependent dimerization, p16INK4A undergoes a dramatic structural rearrangement and forms aggregates that have the typical features of amyloid fibrils, including binding of diagnostic dyes, presence of cross-β sheet structure, and typical dimensions found in electron microscopy. We find that p16INK4A amyloid formation abolishes its function as a CDK4/6 inhibitor in human cells. Taken together, these observations mechanistically link the cellular redox state to the inactivation of p16INK4A through the formation of amyloid fibrils.

2019-09-04 | PXD012353 | Pride

Cellular senescence in malignant cells promotes tumorigenesis in mouse and patient glioblastoma [p16]

Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs and characterize their action on the tumor microenvironment at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared p16-3MR+GCV to WT+GCV control GBMs that were harvested 7 days after the last GCV injection.

2022-12-15 | GSE198439 | GEO

Transcriptional targets of p16INK4A in melanoma

Project description:Expression profiles of 17 melanoma cell lines were analysed to identify genes differentially expressed between cell lines harbouring wild-type or mutant p16INK4A. Relevant paper: Pavey et al. (2007). Note: all of these cell lines contained wild-type p14ARF, so that the transcriptional effects of p16INk4A could be determined without interference from p14ARF. Keywords: Affymetrix Hu133_Plus microarrays

2007-10-01 | GSE7153 | GEO

A Dual Role of the Senescence Marker P16Ink4a in Liver Endothelial Cell Function

Project description:P16Ink4a is a well-established marker of senescence. Although P16Ink4a is expressed in endothelial cells, little is known about its function in these cells. Using isolated liver endothelial cells with silencing or overexpression of P16Ink4a, we show here that dependent on P16Ink4a levels, different pathways and functions are affected. High levels of P16Ink4a reduce proliferation and induce senescence while low levels have the opposite effects. Only high P16Ink4a expression reduces in vitro angiogenesis. Expression profiling reveals an inflammatory phenotype upon silencing of P16Ink4a while P16Ink4a overexpression is associated with a profile associated to DNA damage, repair and senescence. Low levels of P16Ink4a induce reactive oxygen species (ROS) generation and increase endothelial cell leakage. Collectively, P16Ink4a represents an “antagonistic pleiotropy” gene, which is on the one hand required to prevent ROS generation and endothelial damage and on the other hand at high levels inhibits angiogenesis through induction of senescence.

2024-11-18 | GSE281665 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data