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Differentially expressed genes between oncogene-introduced wild-type and Atf4-/- cells

ABSTRACT: During oncogenic transformation, cells acquire genetic mutations that override the normal mechanisms regulating cellular proliferation. Excessive expression of activating transcription factor 4 (ATF4) is often observed in mammalian malignant tumors. However, little is known about the role of ATF4 in the malignant transformation of normal cells. Here, we show that ATF4 promotes oncogene-induced malignant transformation of murine fibroblasts by suppressing the expression of cellular senescence-associated genes. Ectopic expression of oncogenes, H-rasV12 and simian virus 40 large T-antigen, elicited malignant transformation of embryonic fibroblasts from wild-type mice, but not from Atf4-null (Atf4-/-) mice. The oncogenic stresses induced the expression of both Atf4 and cyclin-dependent kinase inhibitor 2a (Cdkn2a), in wild-type cells. Elevated levels of ATF4 successively suppressed the expression of cdkn2a encoding the cellular senescence-associated proteins, p16INK4a and p19ARF, thereby promoting oncogenic transformation. Conversely, the loss of ATF4 caused cellular senescence resulting from the consistent expression of p16INK4a and p19ARF. These findings reveal a novel function of ATF4: that of promoting oncogenic transformation by suppressing cellular senescence. Total 2 samples were derived from [1] H-Ras and SV40T expressing vector-transfected wild-type mouse embryonic fibroblasts (MEFs) and [2] H-Ras and SV40T expressing vector-transfected Atf4-/- MEFs

ORGANISM(S): Mus musculus

SUBMITTER: Satoru Koyanagi

PROVIDER: E-GEOD-31405 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Differentially expressed genes between oncogene-introduced wild-type and Atf4-/- cells

Project description:During oncogenic transformation, cells acquire genetic mutations that override the normal mechanisms regulating cellular proliferation. Excessive expression of activating transcription factor 4 (ATF4) is often observed in mammalian malignant tumors. However, little is known about the role of ATF4 in the malignant transformation of normal cells. Here, we show that ATF4 promotes oncogene-induced malignant transformation of murine fibroblasts by suppressing the expression of cellular senescence-associated genes. Ectopic expression of oncogenes, H-rasV12 and simian virus 40 large T-antigen, elicited malignant transformation of embryonic fibroblasts from wild-type mice, but not from Atf4-null (Atf4-/-) mice. The oncogenic stresses induced the expression of both Atf4 and cyclin-dependent kinase inhibitor 2a (Cdkn2a), in wild-type cells. Elevated levels of ATF4 successively suppressed the expression of cdkn2a encoding the cellular senescence-associated proteins, p16INK4a and p19ARF, thereby promoting oncogenic transformation. Conversely, the loss of ATF4 caused cellular senescence resulting from the consistent expression of p16INK4a and p19ARF. These findings reveal a novel function of ATF4: that of promoting oncogenic transformation by suppressing cellular senescence.

2011-08-17 | GSE31405 | GEO

Expression data from mouse wild type and Trp53-/- Cdkn2a-/- mammary epithelial basal cells

Project description:Three well-known tumor suppressors, TRP53, p16INK4a, and p19ARF (p16INK4a and p19ARF are both coded by the gene Cdkn2a) have been connected to the limiting of stem cell self-renewal and proliferation in some tissues. Here we deposit RNA microarray expression data of sorted mouse Krt14-cre mT/mG Trp53f/f Cdkn2a-/- mammary epithelial basal cells and their wild type control cells (Krt14-cre mT/mG).

2021-01-02 | GSE137573 | GEO

A minimal DNA sequence within the ARF promoter represses p16INK4A expression via long-range chromatin interaction [Cut&Run ChiP-seq]

Project description:Loss of function of CDKN2A/B, also known as INK4/ARF [encoding for p16INK4A, p15INK4B, and p14ARF (mouse p19Arf)]), confers susceptibility to cancers, whereas its up-regulation during organismal aging provokes cellular senescence and tissue degenerative disorders. To better understand molecular regulation of the locus, we knocked P2A-mCherry into the C-terminus of p16INK4A, and this construct faithfully recapitulated the endogenous transcription. Using this reporter cell line, we performed a noncoding tiling pooled screening targeting open chromatin regions spanning the approximately 500-kb region in the topological associated domain that includes p16INK4A. In both Cas9- and dCas9-KRAB–mediated screenings, we identified a 42-bp DNA sequence within exon 1β of the ARF gene, as the repressive element controlling p16INK4A expression. Chromatin conformation capture indicated that inactivating this element abolished the physical interaction between p15INK4B and ARF, thereby abolishing p16INK4A repression. This study has revealed a new mechanism of transcriptional regulation of p16INK4A by long-range chromatin interaction.

2019-12-17 | GSE125841 | GEO

A minimal DNA sequence within the ARF promoter represses p16INK4A expression via long-range chromatin interaction [Capture-C]

2019-12-17 | GSE125666 | 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

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

LSK cells transfected with Hhex retrovirus

Project description:The Hematopoietically-expressed homeobox (Hhex) transcription factor is overexpressed in human myeloid leukemias. Conditional knockout models of murine acute myeloid leukemia (AML) indicate that Hhex maintains leukemia stem cell self-renewal by enabling Polycomb-mediated epigenetic repression of the Cdkn2a tumor suppressor locus, encoding p16Ink4a and p19Arf. However, whether Hhex overexpression also affects hematopoietic differentiation is unknown. To study this, we retrovirally overexpressed Hhex in hematopoietic progenitors. This enabled serial replating of myeloid progenitors, leading to the rapid establishment of IL-3-dependent promyelocytic cell lines. Use of a Hhex-ERT2 fusion protein demonstrated that continuous nuclear Hhex is required for transformation, and structure function analysis demonstrated a requirement of the DNA binding and N-terminal repressive domains of Hhex for promyelocytic transformation. This included the N-terminal Pml interaction domain, although deletion of Pml failed to prevent Hhex-induced promyelocyte transformation, implying other critical partners. Furthermore, deletion of p16Ink4a or p19Arf did not promote promyelocyte transformation, indicating that repression of distinct Hhex target genes is required for this process. Indeed, transcriptome analysis showed that Hhex overexpression resulted in repression of several myeloid developmental genes. To test potential for Hhex overexpression to contribute to leukemic transformation, Hhex-transformed promyelocyte lines were rendered growth factor-independent using a constitutively active IL-3 receptor common b subunit (bcV449E). The resultant cell lines resulted in a rapid promyelocytic leukemia in vivo. Thus Hhex overexpression can contribute to myeloid leukemia via multiple mechanisms including differentiation blockade and enabling epigenetic repression of the Cdkn2a locus.

2018-01-30 | GSE109793 | GEO

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

2009-12-01 | GSE14436 | GEO

Expression data from human primary fibroblasts (IMR90) stably expressing H-RasV12 and shRNA against ERK2 or a non-targeting shRNA

Project description:Oncogenic ras activates several signaling pathways that cooperate in cell transformation. They include the ERK/MAP kinase pathway, the PI3K pathway and the Ral pathway among others. Surprisingly, in primary human fibroblasts, oncogenic ras expression induces senescence not transformation, but upon knockdown of ERK2 senescence is bypassed and transformation is stimulated. We used microarrays to characterize the gene expression programme of cells transformed by oncogenic ras, telomerase and knockdown of the ERK2 kinase. Primary human fibroblasts were co-infected with a retroviral vector that expresses oncogenic ras and either a control shRNA or an shRNA against ERK2. Cells with oncogenic ras and shRNA control entered senescence while cells with oncogenic ras and shRNA ERK2 bypassed senescence and underwent malignant transformation. Triplicates of these populations were used to purify total RNA, which we sent to Genome Quebec service for hybridization with Affymetrix microarrays.

2014-10-01 | E-GEOD-33613 | biostudies-arrayexpress

Bulk RNA-sequencing results of p16INK4A-high and -low glioblastoma, IDH-wild type, grade 4.

Project description:The expression of p16INK4A is widely used to identify fully senescent cells in noncancerous tissues, as well as senescent cancer cells in various types of cancer. In our study, we observed diffuse expression of p16INK4A in around 40 % of the patients with wild-type CDKN2A gene without mutation showing senescence phenotype, correlating with significant differences in overall survival between patients with high and low levels of p16INK4A expression. This prognostic distinction led us to hypothesize that cellular senescence in glioblastoma cells might confer a favorable effect on patient outcomes. To investigate the mechanism underlying this phenotype, we conducted RNA sequencing on 11 samples of glioblastoma, IDH-wild type along with corresponding in vivo and in vitro studies.

2024-05-10 | GSE266210 | GEO

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