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Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

ABSTRACT: Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signalling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here we show that multinucleate OIS cells originated mostly from failed mitosis. Prior to senescence, mutant RasV12 activation in primary human fibroblasts compromised mitosis, associated with abnormal expression of mitotic genes that enter M-phase. Simultaneously, RasV12 activation enhanced survival of damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional up-regulation of Mcl1 was responsible for enhanced slippage of cells with mitotic defects and subsequent cell survival. Importantly, mitotic slippage and oncogene signalling synergistically induced senescence and key senescence regulators p21 and p16. We propose that activated Ras induces transcriptional changes that predispose cells undergoing OIS to mitotic stress and multinucleation. We used RNA-seq of IMR90 cells with inducible expression of oncogenic RasV12 that were synchronised in mitosis, to characterise the nature of mitotic defects that lead to multinucleation of oncogene-induced senescent cells

ORGANISM(S): Homo sapiens

SUBMITTER: Peter Adams

PROVIDER: E-GEOD-70668 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Project description:Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signalling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here we show that multinucleate OIS cells originated mostly from failed mitosis. Prior to senescence, mutant RasV12 activation in primary human fibroblasts compromised mitosis, associated with abnormal expression of mitotic genes that enter M-phase. Simultaneously, RasV12 activation enhanced survival of damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional up-regulation of Mcl1 was responsible for enhanced slippage of cells with mitotic defects and subsequent cell survival. Importantly, mitotic slippage and oncogene signalling synergistically induced senescence and key senescence regulators p21 and p16. We propose that activated Ras induces transcriptional changes that predispose cells undergoing OIS to mitotic stress and multinucleation.

2015-08-13 | GSE70668 | GEO

BRD7 is a candidate tumour suppressor gene required for p53 function

Project description:Oncogene-induced senescence (OIS) is a p53-dependent defence mechanism against uncontrolled proliferation. Consequently, many human tumours harbour p53 mutations while others show a dysfunctional p53 pathway, frequently by unknown mechanisms. We identified BRD7, a bromodomain-containing protein whose inhibition allows full neoplastic transformation in the presence of wild-type p53. Intriguingly, in human breast tumours harbouring wild-type, but not mutant p53, the BRD7 gene locus was frequently deleted and low BRD7 expression was found in a subgroup of tumours. Functionally, BRD7 is required for efficient p53-mediated transcription of a subset of target genes. BRD7 interacts with p53 and p300, and is recruited to target gene promoters, affecting histone acetylation, p53 acetylation, and promoter activity. Thus, BRD7 suppresses tumourigenicity by serving as a p53 cofactor required for efficient induction of p53-dependent OIS. We recorded mRNA expression profiles of BJ primary fibroblasts expressing the oncogene RasV12 and either control vector, one of two BRD7 knockdown vectors, or p53 knockdown vector. In addition, we profiled genome-wide protein DNA interactions for p53 and BRD7 using ChIP-Seq. p53- and BRD7-binding sites were recorded in RasV12-expressing BJ cells; as a control we used knockdown of the gene of interest (BRD7 or p53).

2010-03-14 | E-GEOD-20076 | biostudies-arrayexpress

Influence of C/EBPβ 3'UTR on RasV12 induced gene expression

Project description:C/EBPb is an auto-repressed protein that becomes posttranslationally activated by Ras-MEK-ERK signalling. C/EBPb is required for oncogene-induced senescence (OIS) of primary fibroblasts, but also displays pro-oncogenic functions in many tumour cells. Here, we show that C/EBPb activation by H-RasV12 is suppressed in immortalized/transformed cells, but not in primary cells, by its 30 untranslated region (30UTR). 30UTR sequences inhibited Ras-induced cytostatic activity of C/EBPb, DNA binding, transactivation, phosphorylation, and homodimerization, without significantly affecting protein expression. The 30UTR suppressed induction of senescence-associated C/EBPb target genes, while promoting expression of genes linked to cancers and TGFb signalling. An AU-rich element (ARE) and its cognate RNA-binding protein, HuR, were required for 30UTR inhibition. These components also excluded the Cebpb mRNA from a perinuclear cytoplasmic region that contains activated ERK1/2, indicating that the site of C/EBPb translation controls de-repression by Ras signalling. Notably, 30UTR inhibition and Cebpb mRNA compartmentalization were absent in primary fibroblasts, allowing Ras-induced C/EBPb activation and OIS to proceed. Our findings reveal a novel mechanism whereby non-coding mRNA sequences selectively regulate C/EBPb activity and suppress its anti-oncogenic functions. NIH-3T3 cells were retrovirally infected and selected with appropriate antiobiotics. Equal number of cells were plated and collected 48-72 hours later.

2011-07-22 | E-GEOD-30834 | biostudies-arrayexpress

Histone H3.3 and its proteolytically processed form drive a cellular senescence program

Project description:In this study, we have uncovered novel proteolytic processing of the histone H3 tail in senescence models in primary fibroblasts and melanocytes. Cleavage of H3 tail occurs at two distinct residues and is mediated by Cathepsin L. We show that variant H3.3 is preferentially cleaved, and that cleaved histones are associated with chromatin and incorporated into nucleosomes. We also found that the histone chaperone ASF1a is required for chromatin incorporation of the cleaved histone species. Further, we show that overexpression of cleaved H3.3 induces a senescence program in fibroblasts in the absensence of oncogenic signaling. For the RNA-seq studies, growing IMR90 fibroblasts were compared to cells induced to senesce via oncogene activation or cleaved H3.3 overexpression. Growing controls consist of IMR90 cells infected with empty retroviral construct pBabe and grown under normal conditions for 13 days prior to RNA isolation. For oncogene-induced senescence samples, IMR90s carrying a tamoxifen-inducible H-RasV12 retroviral construct were induced to senesce by addition of 10nM tamoxifen to the media for 8 days. Finally, IMR90s were infected with a retroviral construct expressing the cleaved form of H3.3 with a C-terminal Flag tag. RNA samples form this group were isolated at days 3 (early) and 13 (late) post-infection. In all cases, total RNA samples were isolated using RNeasy kit (Qiagen) and prepared at the Icahn School of Medicine at Mount Sinai Genomics Core Facility for poly A library construction and sequencing on IlluminaHiSeq 2500.

2014-10-01 | E-GEOD-55949 | biostudies-arrayexpress

Unbiased identification of CSDE1-regulated targets during oncogene-induced senescence [RNA-Seq-sh]

Project description:We show that the RNA-binding protein CSDE1/UNR promotes oncogene-induced senescence (OIS) in primary mouse keratynocytes challenged by over-expression of H-RASv12. Depletion of CSDE1 leads to senescence bypass, cell immortalization and tumor formation. Combining individual nucleotide cross-linking and immunoprecipitation (iCLIP), RNA-seq and polysome profiling followed by functional studies, we identify targets regulated by CSDE1 and uncover the downstream molecular mechanisms.

2022-01-11 | GSE160000 | GEO

Unbiased identification of CSDE1-regulated targets during oncogene-induced senescence [RNA-Seq]

2022-01-11 | GSE159999 | GEO

Unbiased identification of CSDE1-regulated targets during oncogene-induced senescence [polysome profiling]

2022-01-11 | GSE159998 | GEO

Unbiased identification of CSDE1-regulated targets during oncogene-induced senescence [i-CLIP]

2022-01-11 | GSE159997 | GEO

Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1

Project description:Telomeres play crucial roles during tumorigenesis inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alters telomeric chromatin composition and function. Here we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveals upregulation of proteins involved in chromatin remodeling, DNA repair and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.

2018-07-13 | PXD010088 | Pride

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

Project description:Oncogenic signals can induce premature senescence (OIS) in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. In order to identify new regulators of OIS, we performed a loss-of-function genetic screen and identified that the loss of SCN9A sodium channel allowed cells to escape from OIS. Here we studied the transcriptome profiles of an OIS model based on human mammary epithelial cells stably expressing hTert to be immortalized and MEK:ER, a 4-hydroxytamoxifen (4-OHT) inducible oncogene MEK:ER (HEC-TM cells), to induce the oncogenic signal. We used an shRNA in order to knockdown SCN9A expression during OIS, and KCL treatment to study the impact of membrane depolarization on senescence induction. We showed that SCN9A and plama membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence. Taken together, our work delineates a new pathway, which involves the NFkB transcription factor, SCN9A expression, plasma membrane depolarization.

2018-02-21 | GSE110884 | GEO

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