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Development of MDM2-targeting PROTAC technology for advancing bone regeneration

ABSTRACT: Development of MDM2-targeting PROTAC technology for advancing bone regeneration

PROVIDER: PRJNA1074395 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27907722_1.fastq.gz	Fastqsanger.gz
	SRR27907722_2.fastq.gz	Fastqsanger.gz
	SRR27907723_1.fastq.gz	Fastqsanger.gz
	SRR27907723_2.fastq.gz	Fastqsanger.gz
	SRR27907724_1.fastq.gz	Fastqsanger.gz

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Development of MDM2-targeting PROTAC technology for advancing bone regeneration

Project description:MDM2 inhibitor remarkably induced biomineralization in hDPSCs but it remained the problem that p53 activation is insufficient due to MDM2-p53 autoregulatory feedback loop. To overcome the limitation of the MDM2 inhibitors, we applied proteolysis targeting chimera (PROTAC), a technology that degrades a protein of interest (POI) by intracellular ubiquitin-proteasome system. Hence, we propose a strategy to induce hard tissue regeneration by MDM2-targeting PROTAC technology. We selected Nutlin-3 of POI ligand among various MDM2 inhibitors based on the screening process, and the selected CRBN of E3 ligase ligand. The MDM2-PROTAC synthesis platform was designed by each ligand combination. By performing the degradation test for selected compounds, we evaluated the characteristics of the developed MDM2 PROTAC such as the maximal degradation concentration (DCmax), the half of maximal degradation concentration (DC50), and half-lifetime. To investigate gene expression profiling of MDM2-targeting small molecules, we conducted RNA-sequencing under MDM2 PROTAC and Nutlin-3 (POI ligand) treated conditions. We not only confirmed a robust effect on biomineralization by MDM2-targeting small molecules but also demonstrated the potent osteogenic differentiation ability of MDM2 PROTAC when compared to an MDM2 inhibitor. MDM2-PROTAC significantly increased mRNA levels of osteogenic differentiation marker genes. Also, the significant bone generation effect of MDM2 PROTAC was validated in an ovariectomy (OVX)-induced osteoporosis animal model. Through these results, it is expected that a new therapeutic modality for hard tissue regeneration will be possible, and the application range of the PROTAC system can be expanded.

2024-06-11 | GSE255297 | GEO

Proteomics Data for MDM2-targeting PROTACs in MDM2-Overexpressing HeLa Cells

Project description:Data files associated with the manuscript titled "Development of MDM2-targeting PROTAC for Advancing Bone Regeneration," which is currently under review. This manuscript introduces MDM2-targeting PROTACs specifically designed for applications in bone regeneration. We developed MDM2-PROTACs (CL144) that demonstrated potent degradation efficiency and a strong inductive effect on biomineralization. Proteomics analysis was conducted on HeLa cells overexpressing MDM2 to investigate the degradation selectivity of the compound. From the proteomics database search, we identified 8,353 proteins and observed the downregulation of several ubiquitin ligases and processing proteins, including USP29, USP48, RBX1, and ZNF598, in the HeLa cell experiment.

2025-02-12 | MSV000097107 | MassIVE

Proteomics Data for MDM2-targeting PROTACs in hBMSCs

Project description:Data files associated with the manuscript titled "Development of MDM2-targeting PROTAC for Advancing Bone Regeneration," which is currently under review. This manuscript introduces MDM2-targeting PROTACs customized for application in bone regeneration. We developed MDM2-PROTACs (CL144) that demonstrated potent degradation efficiency and a strong inductive effect on biomineralization. Proteomics analysis was performed on human bone marrow-derived mesenchymal stem cells (hBMSCs) to investigate the degradation selectivity of the compound. Through proteomics database searches, we identified 6,388 proteins, including several differentially expressed proteins (DEPs), many of which are known to interact with MDM2 or play significant roles in the ubiquitin-proteasome system.

2025-02-12 | MSV000097106 | MassIVE

Development of MDM2-Targeting PROTAC for Advancing Bone Regeneration.

Project description: Not available

| S-EPMC12097015 | biostudies-literature

MDM2 binds and suppresses RNA polymerase III to restrain the innate immune response to cytosolic DNA

Project description:The oncoprotein MDM2 is widely recognized as the principal negative regulator of p53, thereby controlling the expression of numerous RNA polymerase II (Pol II)-dependent genes involved in cell cycle arrest and apoptosis. Beyond this canonical role, MDM2 also engages in transcriptional regulation independently of p53, for instance through interactions with polycomb repressor complexes. Here, we identify RNA polymerase III (Pol III) as an additional target of MDM2 function. Using two complementary chemical tools – a small-molecule MDM2 antagonist (MI-1061) that releases p53 and augments MDM2 expression, and a PROTAC degrader (MD-224) that simultaneously activates p53 and promotes MDM2 ubiquitination and proteasomal destruction – we dissected the role of MDM2 in cells with amplified MDM2. Elevated MDM2 suppressed the transcription of Pol III-dependent genes encoding tRNA or 5S ribosomal RNA. Mechanistically, we found the aminoterminal domain of MDM2 associated with the catalytic subunit of Pol III, revealing a molecular link between MDM2 and the Pol III machinery. Because Pol III also acts as a cytosolic DNA sensor that converts DNA into double-stranded RNA to trigger RIG-I–TBK1–IRF3–dependent signaling, we asked whether MDM2 modulates this pathway. Indeed, enhanced MDM2 expression markedly attenuated the induction of innate immunity genes such as CXCL10, OAS1, and MX1 following transfection with Poly(dA:dT). Similarly, DNA damage induced by a radiomimetic agent activated Pol III–dependent innate signaling, and this was again blunted by high MDM2 levels, resulting in enhanced cell survival. Taken together, our findings establish MDM2 as a previously unrecognized suppressor of Pol III–dependent transcription in response to cytosolic DNA. This expands the repertoire of MDM2 functions beyond repression of p53 and Pol II activity, positioning MDM2 as a broad regulator of transcription and innate immunity.

2026-08-06 | GSE334227 | GEO

MDM2 binds and suppresses RNA polymerase III to restrain the innate immune response to cytosolic DNA

2026-08-06 | GSE333484 | GEO

Harnessing PROTAC technology to combat stress hormone receptor activation

Project description:We want to quantify the proteome alteration following PROTAC mediated Glucocorticoid receptor depletion in vitro.

2023-12-11 | PXD046949 | Pride

Targeting STAT3 with Conditional Knockout or PROTAC Technology Alleviates Renal Injury by Limiting Pyroptosis [RNA-seq]

Project description:Targeting STAT3 with Conditional Knockout or PROTAC Technology Alleviates Renal Injury by Limiting Pyroptosis [RNA-seq]

| PRJNA1192256 | ENA

Targeting STAT3 with Conditional Knockout or PROTAC Technology Alleviates Renal Injury by Limiting Pyroptosis [ChIP-seq]

Project description:Targeting STAT3 with Conditional Knockout or PROTAC Technology Alleviates Renal Injury by Limiting Pyroptosis [ChIP-seq]

| PRJNA1192260 | ENA

PROTAC repurposing uncovers a noncanonical binding surface that mediates chemical degradation of nuclear receptors

Project description:MD-224 is a PROTAC that induces degradation of the human protein MDM2. However, we have found that it also induces degradation of a subset of nuclear receptors. DIA was performed to assess the overall specificity of MD-224 in 293T cells and the colorectal cancer cell line SNU-C4.

2025-09-18 | PXD066110 | Pride

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