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RNF4-RGMb axis is required for osteogenic differentiation and cancer cell survival

ABSTRACT: RNF4-RGMb axis is required for osteogenic differentiation and cancer cell survival

PROVIDER: PRJNA845209 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19537647.fastq.gz	Fastqsanger.gz
	SRR19537648.fastq.gz	Fastqsanger.gz
	SRR19537649.fastq.gz	Fastqsanger.gz
	SRR19537650.fastq.gz	Fastqsanger.gz
	SRR19537651.fastq.gz	Fastqsanger.gz

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RNF4-RGMb axis is required for osteogenic differentiation and cancer cell survival

Project description:Molecular understanding of osteogenic differentiation (OD) of human bone-marrow derived mesenchymal stem cells (hBMSCs) is important for regenerative medicine and has direct implications to cancer. Here we report that the RNF4 ubiquitin ligase is essential for OD of hBMSCs, and that RNF4 deficient hBMSCs fail to differentiate and remain as stalled progenitors. Remarkably, addition of media from differentiating hBMSCs to RNF4-deficient MSCs alleviated the block in OD. Transcriptional analysis of RNF4-dependent gene signature identified two secreted factors; BMP6 and the guidance molecule BMP6 co-receptor RGMb (Dragon). Knockdown of either RGMb or BMP6 in hBMSCs inhibit differentiation, and only the combined addition of purified RGMb and BMP6 proteins to RNF4-deficient MSCs fully restored osteogenic differentiation. Moreover, RNF4-RGMb axis is highly relevant cancer cell survival and tumorigenicity, including osteosarcoma and Therapy-resistant melanoma cells. In accordance, in human melanoma biopsies high level of RGMb correlates with high level of RNF4, and is associated with resistance to molecular therapy and poor prognosis of patients. Thus, RNF4~BMP6~RGMb is a molecular axis that is key for OD and tumorigenesis.

2022-09-28 | GSE205432 | GEO

RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival.

Project description: Not available

| S-EPMC9509360 | biostudies-literature

Identification of RNF4 dependent gene signature in melanoma tumors

Project description:Among hallmarks of cancer is impaired proteostasis, that is characterized by increased oncoprotein stability. Here we demonstrate that RNF4, a ubiquitin ligase implicated in the stabilization of short-lived oncoproteins, is important for melanoma tumorigenesis. High levels of RNF4 in melanoma patient-derived specimens coincide with poor prognosis. Accordingly, RNF4, is essential for the growth and migration and survival of melanoma cells, both in culture and in xenograft models. RNA-seq analyses of RNF4-expressing tumors identified a gene signature related to melanoma growth and migration. Among the upstream regulators of RNF4-dependent gene signature are c-Myc and HIF1a which exhibit elevated protein levels that also coincided with stabilization of the translation initiation regulator p-eIF2a. Correspondingly, the effects of RNF4 on melanomagenesis are p-eIF2a-dependent, thus highlighting an unexpected regulatory axis in melanoma via RNF4-and ubiquitin-dependent protein stabilization

2021-05-05 | GSE124064 | GEO

Effect of RNF4 depletion on GSK3685032-induced gene expression changes in MV4-11 cells [RRBS]

Project description:GSK3685032-induced DNA hypomethylation results in upregulation of largely viral-responsive gene expression pathways and cell death. We identified that loss of RNF4 causes resistance to GSK3685032. We established RNF4 wild type and deficient MV4-11 cells by CRISPR-Cas9 disruption and treated with vehicle or GSK3685032 to determine how RNF4-deficiency impacts GSK3685032-induced gene expression changes

2026-05-17 | GSE233727 | GEO

RNF4-knockdown and RNF4-TULIP identified proteins

Project description:In this project we aim to identify the spacific targets of the SUMO-Targeted Ubiquitin Ligase (STUBL) RNF4. For that, we combine the study of SUMOylation targets that are enriched after RNF4 knockdown with the use of Targeted Ubiquitin Ligases Identified by Proteomics (TULIP).

2017-11-23 | PXD005425 | Pride

Effect of RNF4 depletion on GSK3685032-induced chromatin accessibilty changes in MV4-11 cells [ATAC-seq]

2026-05-17 | GSE233725 | GEO

Effect of RNF4 depletion on GSK3685032-induced gene expression changes in MV4-11 cells [RNA-seq]

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Whole cell proteome of HeLa Flp in T-RexTM RNF4 WT treated with either CCW16, 1a or 2c

Project description:The SUMO-targeted E3 ubiquitin ligase RNF4 plays an important role in safeguarding genome and proteome integrity. RNF4 recognizes polySUMO modified proteins and induces their proteolytic or non-proteolytic ubiquitylation. Based on the key functions of RNF4 maintaining proteome and genome stability, control of DNA damage response and DNA-protein crosslink repair, we explored its role in cancer cell survival and as a potential drug target. We found that RNF4 is overexpressed in acute myeloid leukemia and expression levels correlate with poor survival. To develop PROTACs for targeted degradation of RNF4, we aimed to exploit the recently developed cysteine-reactive RNF4 ligand CCW16, and synthesized a set of CCW16-derived degrader molecules using established VHL- and CRBN E3 ligands. We showed that treatment with two CCW16-derived PROTACs leads to overexpression of HMOX1, a ferroptosis marker, and HSP70 protein family members. However, we could not detect a significant reduction of RNF4 levels. Interestingly, also the RNF4 binder CCW16 itself induced the expression of HMOX1. Altogether our data indicates that treatment with CCW16 leads to a ferroptotic cell death pathway.

2025-10-13 | PXD056951 | Pride

RNF4 interactome in heatshocked HeLa cells

Project description:Exposure of cells to heat or oxidative stress causes misfolding of proteins. To avoid toxic protein aggregation, cells have evolved nuclear and cytosolic protein quality control (PQC) systems. In response to proteotoxic stress cells also limit protein synthesis by triggering transient storage of mRNAs and RNA binding proteins (RBPs) in cytosolic stress granules (SGs). We demonstrate that the SUMO-targeted ubiquitin ligase (StUbL) pathway, which is part of the nuclear proteostasis network, regulates SG dynamics. We provide evidence that inactivation of SUMO deconjugases under proteotoxic stress initiates SUMO-primed, RNF4-dependent ubiquitylation of RBPs that typically condense into SGs. Impairment of SUMO-primed ubiquitylation drastically delays SG resolution upon stress release. Importantly, the StUbL system regulates compartmentalization of an amyotrophic lateral sclerosis (ALS)-associated mutant of FUS in SGs. We propose that the StUbL system functions as surveillance pathway for aggregation-prone RBPs in the nucleus thereby linking the nuclear and cytosolic axis of proteotoxic stress response. To better understand the role of RNF4 in the proteotoxic stress response we aimed to identify RNF4-associated protein complexes in cells exposed to heat stress. To allow immuno-affinity purification of endogenous RNF4 on anti-Flag agarose beads we used CRISPR/Cas9-mediated gene editing to integrate a C-terminal 3xFlag epitope tag into the genomic locus of RNF4 in HeLa cells. For the IP-MS experiment HeLa-RNF4-3xFlag cells or parental untagged control cells were exposed to heat stress for 1 h and RNF4-3xFlag together with associated proteins was captured on anti-Flag affinity beads. Tryptic peptides were analyzed by LC-MS/MS and data from three replicates were quantified by the Max Quant label-free quantification (LFQ) algorithm.

2023-06-30 | PXD017888 | Pride

HNRNPH1 is required for rhabdomyosarcoma cell growth and survival

Project description:HNRNPH1 is required for rhabdomyosarcoma cell growth and survival

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