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ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE217767 | GEO | 2024/10/10

REPOSITORIES: GEO

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ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:In this study, we found that the ARF tumor suppressor directly binds the PAF1 subunit to block the assembly of PAF1 complex (PAF1c) and its interaction with RNAPII, thereby dampening PAF1c-dependent transcription in vitro and in cells. Using RNA-seq of control (shNT) and ARF knockdown (shARF) mouse embryonic fibroblasts (MEFs) we first define transcriptome changes upon ARF loss. Through downstream mechanistic analysis we then validate direct ARF-mediated inactivation of PAF1c-dependent RNAPII transcription and their cellular consequences.

2024-10-10 | GSE217766 | GEO

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:In this study, we found that the ARF tumor suppressor directly binds the PAF1 subunit to block the assembly of PAF1 complex (PAF1c) and its interaction with RNAPII, thereby dampening PAF1c-dependent transcription in vitro and in cells. To investigate whether ARF regulates RNAPII and PAF1c occupancy at putative target genes identified through RNA-seq, we performed ChIP-seq (RNAPII, PAF1, and CTR9) in ARF (shARF) vs. control (shNT) knockdown MEFs. Our data show that loss of ARF increases RNAPII, PAF1, and CTR9 occupancy on upregulated genes, consistent with ARF-mediated gene-specific repression. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for RNA polymerase subunit RPB3 and PAF1 complex subunits PAF1 and CTR9 in mouse embryonic fibroblasts.

2024-10-10 | GSE217765 | GEO

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

| PRJNA900287 | ENA

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

| PRJNA900286 | ENA

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

| PRJNA900284 | ENA

ARF alters PAF1 complex integrity to selectively restrain a pro-growth transcriptional program to tune cell proliferation

Project description:Sample 1: LUM2_875391: IgG, as negative control Sample 2: LUM2_875392: ARF IP

2023-04-12 | MSV000091694 | MassIVE

ARF alters PAF1 complex integrity to selectively restrain a pro-growth transcriptional program to tune cell proliferation

Project description:Sample 1, LUM2_920735: GFP:FLAG, as negative control Sample 2, LUM2_920736: ARF:FLAG (untreated) Sample 3, LUM2_920737: ARF:FLAG (with DNase treatment) Sample 4, LUM2_920738: ARF:FLAG (with RNase treatment)

2023-02-06 | MSV000091209 | MassIVE

Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses.

Project description:The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings, suggesting that the ARF-p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress.

| S-EPMC3737736 | biostudies-literature

ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis.

Project description:The ARF and p53 tumor suppressors are thought to act in a linear pathway to prevent cellular transformation in response to various oncogenic signals. Here, we show that loss of p53 leads to an increase in ARF protein levels, which function to limit the proliferation and tumorigenicity of p53-deficient cells by inhibiting an IFN-β-STAT1-ISG15 signaling axis. Human triple-negative breast cancer (TNBC) tumor samples with coinactivation of p53 and ARF exhibit high expression of both STAT1 and ISG15, and TNBC cell lines are sensitive to STAT1 depletion. We propose that loss of p53 function and subsequent ARF induction creates a selective pressure to inactivate ARF and propose that tumors harboring coinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation.

| S-EPMC4157460 | biostudies-literature

A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2.

Project description:The tumour suppressor ARF (alternative reading frame) is encoded by the INK4a (inhibitor of cyclin-dependent kinase 4)/ARF locus, which is frequently altered in human tumours. ARF binds MDM2 (murine double minute 2) and releases p53 from inhibition by MDM2, resulting in stabilization, accumulation and activation of p53. Recently, ARF has been found to associate with other proteins, but, to date, little is known about ARF-associated proteins that are implicated in post-translational regulation of ARF activity. Using a yeast two-hybrid screen, we have identified a novel protein, LZAP (LXXLL/leucine-zipper-containing ARF-binding protein), that interacts with endogenous ARF in mammalian cells. In the present study, we show that LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity towards p53, but simultaneously co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional activity. Expression of LZAP, in addition to ARF, increased the percentage of cells in the G1 phase of the cell cycle. Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle arrest in the absence of ARF. Taken together, our data suggest that LZAP can regulate ARF biochemical and biological activity. Additionally, LZAP has p53-dependent cell-cycle effects that are independent of ARF.

| S-EPMC1360699 | biostudies-literature

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