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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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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

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

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells [Bisulfite-seq]

Project description:We acutely depleted the BCL11A protein by using the dTAG PROTAC technology, and assessed its immediate consequences on DNA methylation at the HBG1/2 promoter region.

2022-07-19 | GSE194344 | GEO

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells [PRO-seq washout]

Project description:We acutely depleted the BCL11A protein by using the dTAG PROTAC technology, then performed a drug washout and and assessed its immediate consequences nascent transcription.

2022-07-19 | GSE194347 | GEO

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells [DNA methylation]

Project description:We acutely depleted the BCL11A protein by using the dTAG PROTAC technology, and assessed its immediate consequences on DNA methylation, in the presence/absence of DNMT1 inhibitor AZAcytidine.

2022-07-19 | GSE194340 | GEO

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells [PRO-seq early]

Project description:We acutely depleted the BCL11A protein by using the dTAG PROTAC technology, and assessed its immediate consequences on nascent transcription, DNA methylation, Protein expression and HIstone modification and chromatin accessibility.

2022-07-19 | GSE194345 | GEO

Genome-wide maps of chromatin binding site for Mdm2.

Project description:The MDM2 oncoprotein is an essential component of the p53 pathway. Although MDM2 has been widely described as a major negative regulator of the p53 tumor suppressor, growing evidences support the notion that Mdm2 functions are also mediated through p53 independent mechanisms. We found that MDM2 is recruited on chromatin. By ChIP-Seq (using MDM2 antibody) of H1299 cells exhibiting MDM2 recruitment on chromatin, we identified at the whole genome level MDM2 binding sites. Both input and IPped-DNA were exhaustively sequenced and mapped on human genome

2016-06-09 | GSE64439 | GEO

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells [ChIP-seq]

Project description:We acutely depleted the BCL11A protein by using the dTAG PROTAC technology, and assessed its consequences on histone modification by ChIP-seq,and compared this to changes in nascent transcription, DNA methylation, Protein expression and chromatin accessibility.

2022-07-19 | GSE194342 | GEO

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells [ATAC-seq]

Project description:We acutely depleted the BCL11A protein by using the dTAG PROTAC technology, and assessed its immediate consequences on chromatin accessibility by ATAC-seq,and compared this to changes in nascent transcription, DNA methylation, Protein expression and HIstone modification.

2022-07-19 | GSE194339 | GEO

Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

Project description:Although amplification/overexpression is the predominant mechanism for the oncogenic properties of MDM2, an increasing number of MDM2 somatic missense mutations were identified in cancer patients with the recent advances in sequencing technology. Here, we characterized an MDM2 cancer-associated mutant variant W329G identified from patient samples that contain a wild-type p53 gene. We found that the MDM2 W329G mutant was resistant to the inhibitory effect of ribosomal protein L11 (RPL11) on MDM2-mediated p53 ubiquitination and degradation, in line with its defect on RPL11 binding. Using isogenic U2OS cells with or without endogenous mdm2 W329G mutation, we demonstrated that the expression of classic p53 targets induced by ribosomal stress signals was reduced in mutant cells. RNA-seq analysis revealed that upon 5-FU treatment, the p53 response was significantly impaired. Also, the 5-FU-mediated repression of genes in cell cycle progression and DNA replication was diminished in W329G mutant-containing cells. Physiologically, U2OS W329G cells were more resistant to cell growth inhibition induced by ribosomal stress and exhibited higher glycolytic rates upon 5-FU treatment. Together, our data indicated that cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

2024-05-13 | GSE267150 | GEO

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