bims-midomi 2026-05-17 papers

Cells. 2026 May 01. pii: 831. [Epub ahead of print]15(9):

MDM2 Drives Proteasome Inhibitor Resistance and Represents a TP53-Independent Therapeutic Vulnerability in Multiple Myeloma.

María Labrador, Sara Cozzubbo, Mariangela Porro, Michela Cumerlato, Cecilia Bandini, Elisabetta Mereu, Tina Paradzik, Benedetta Donati, Veronica Manicardi, Domenica Ronchetti, Mattia D'Agostino, Alessandra Larocca, Francesca Gay, Benedetto Bruno, Alessia Ciarrocchi, Andrew Chatr-Aryamontri, Antonino Neri, Eugenio Morelli, Roberto Piva.

Proteasome inhibitors (PIs) are central to multiple myeloma (MM) therapy; however, resistance remains a major clinical challenge, particularly in relapsed/refractory disease. To identify functional mediators of carfilzomib (CFZ) resistance, we performed complementary gain-of-function CRISPR activation and pharmacological screening approaches. These unbiased strategies converged on the E3 ubiquitin ligase MDM2 as a modulator of PI response. MDM2 transactivation enhanced MM cell survival and accelerated recovery following CFZ exposure, supporting a causal role in proteotoxic stress tolerance. Pharmacologic inhibition of MDM2 with NVP-CGM097 synergized with CFZ across multiple PI-sensitive and PI-resistant MM cell lines, irrespective of TP53 status. Mechanistically, MDM2 inhibition induced p21 upregulation, cell-cycle arrest, and reduced c-MYC expression, accompanied by impaired activation of DNA damage response mediators. Genetic silencing of MDM2 phenocopied these effects and increased CFZ sensitivity. Importantly, the combination retained efficacy in MM-stromal co-culture models and in primary patient samples, including cases harboring del(17p), while sparing normal peripheral blood mononuclear cells. Collectively, these findings identify MDM2 as a functional driver of PI resistance and support combined MDM2 and proteasome inhibition as a rational therapeutic strategy in MM, including TP53-deficient contexts.

Keywords: MDM2; TP53; drug resistance; multiple myeloma; proteasome inhibitors; synthetic lethality

DOI: https://doi.org/10.3390/cells15090831

Biochemistry. 2026 May 14.

Integrative Modeling Identifies a Dual-Function Helix in Full-Length MDM2, Providing Novel Mechanistic Insights.

Hariom Chaudhary, Archna Pandey, Rimpy Kaur Chowhan.

The E3 ubiquitin ligase MDM2, an important oncogene, is a central negative regulator of p53, yet its extensive intrinsically disordered regions have hindered structural characterization of the full-length protein. Here, we integrate AlphaFold ensemble modeling to sample the conformational landscape with all-atom molecular dynamics simulations to characterize structural stability and construct a comprehensive, dynamic model of full-length MDM2. Our analysis identifies a previously uncharacterized autoinhibitory helix (upstream of the central acidic domain) in MDM2 that dynamically masks the N-terminal p53-binding pocket. The dynamic ensembles reveal a multistep unmasking pathway in which the helix pivots away to expose the buried p53-binding pocket. This is followed by a stabilization mechanism whereby, in the bound complex, the same helix repositions to act as an adaptive clamp, anchoring the docked p53. Our study indicates this dynamic gating apparatus to be evolutionarily conserved among MDM2 homologues. These findings provide an atomic-level framework for understanding how MDM2's intrinsic dynamics regulate p53 recognition and suggest new avenues for therapeutic targeting of the p53-MDM2 axis.

DOI: https://doi.org/10.1021/acs.biochem.6c00105

Cell Biol Toxicol. 2026 May 09.

The role of e3 ubiquitin ligases and deubiquitinating enzymes in hepatocellular carcinoma.

Lei Wang, Hongyan Zhang, Yue Hu, Xingqiang Li, Jing Liu, Ying Liang.

Ubiquitination, a key post-translational modification, is responsible for regulating protein stability, activity, subcellular localization, and interactions via the ubiquitin-proteasome system (UPS). The UPS plays a role in non-lysosomal protein degradation, involved in the coordinated action of ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). The review elaborates on the functions of key E3 ligases of MDM2, β-TrCP, and SCF complexes, which modulate cell cycle progression, apoptosis, metabolic reprogramming, and drug resistance in hepatocellular carcinoma (HCC). For instance, MDM2 promotes HCC development by degrading the tumor suppressor p53, while β-TrCP influences the Wnt/β-catenin signaling axis by changing β-catenin levels. Deubiquitinating enzymes (DUBs), including the USP family and CYLD, also play significant roles in HCC by stabilizing or destabilizing critical proteins involved in oncogenesis. The clinical potential of ubiquitination-related molecules as biomarkers for predicting HCC prognosis and as therapeutic targets is also discussed. This review comprehensively examines the role of ubiquitination modification in HCC and its clinical relevance. Future research directions include the exploration of novel ubiquitination modifications, their interactions with other post-translational modifications, and the development of precision medicine strategies based on multi-omics technologies to improve HCC treatment outcomes.

Keywords: Deubiquitinating enzymes; E3 ubiquitin ligases; Hepatocellular carcinoma; Ubiquitination

DOI: https://doi.org/10.1007/s10565-026-10192-1