bims-midomi 2026-03-15 papers

Cells. 2026 Feb 27. pii: 415. [Epub ahead of print]15(5):

Hepatitis C Virus Core Induces p53 Ser-15 Phosphorylation to Facilitate E6-Associated Protein-Mediated Proteasomal Degradation of p53.

Hyunyoung Yoon, Ji-Min Park, Jiwoo Han, Yerin Kwon, Kyung Lib Jang.

The hepatitis C virus (HCV) Core activates the ATM-Chk2 pathway, leading to phosphorylation of p53 at Ser-15, which inhibits mouse double minute 2 (MDM2)-mediated proteasomal degradation. This study reveals that HCV Core also promotes E6-associated protein (E6AP)-mediated degradation of p53 during HCV replication. In the presence of HCV Core, E6AP expression induced p53 ubiquitination, reduced its stability, and decreased p53 levels, whereas E6AP knockdown increased p53 levels. The E3 ubiquitin ligase activity of E6AP was critical for this process, as demonstrated using the E6AP C833A mutant and the E3 ligase inhibitor Heclin. Proteasomal inhibition with MG132 confirmed that HCV Core and E6AP act together to regulate p53 levels via the proteasome. Importantly, HCV Core-induced p53 phosphorylation was essential for E6AP-mediated degradation, as shown by the impairment of degradation in the presence of the ATM inhibitor KU-55933. E6AP also targeted p53 phosphorylated at Ser-15 by etoposide, as well as phosphomimetic mutants such as p53 S15D, but not non-phosphorylatable mutants such as p53 S15A. These findings suggest that HCV Core-induced p53 phosphorylation enhances E6AP-mediated degradation while preventing MDM2 from targeting p53, thereby maintaining p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes.

Keywords: E6-assocoated protein; MDM2; core protein; hepatitis C virus; p53; proteasomal degradation; ubiquitination

DOI: https://doi.org/10.3390/cells15050415

Cells. 2026 Mar 05. pii: 473. [Epub ahead of print]15(5):

PROTAC-Mediated Targeted Degradation of MDM2 Induces Tumor-Suppressive Signaling in Osteosarcoma Cells.

Yeongji Kim, Jin-Woo Kim, Junwon Choi, Jinhyeong Kim, Soyeon Park, Wonji Choi, Hyunju An, Jinman Kim, Minsup Kim, Sujin Choi, Jinsu Lim, Hyun Il Lee, Soonchul Lee.

Osteosarcoma, the most common malignant bone tumor in young individuals, often exhibits poor outcomes due to MDM2-mediated suppression of the p53 pathway. Whereas conventional MDM2 inhibitors block the p53-MDM2 interaction but frequently induce compensatory MDM2 upregulation, proteolysis-targeting chimeras (PROTACs) directly degrade MDM2 and bypass this limitation. Here, we investigated the anticancer efficacy of two MDM2-targeting PROTAC compounds, CL0144 and CL0174, in osteosarcoma models. In Saos-2 and U2OS cells, both PROTACs efficiently induced MDM2 degradation, leading to activation of p53 or p73 signaling, increased reactive oxygen species production, apoptotic cell death, and marked reductions in viability. PROTAC treatment also significantly suppressed proliferation, colony formation, sphere formation, migration, and invasion. In vivo, xenograft assays demonstrated robust tumor growth inhibition following PROTAC administration. Collectively, these findings demonstrate that MDM2-targeting PROTACs exert strong antitumor effects by degrading MDM2 and disrupting downstream oncogenic pathways, supporting their potential as a promising therapeutic strategy for osteosarcoma.

Keywords: MDM2 degradation; PROTAC; cancer therapy; osteosarcoma; p53 pathway

DOI: https://doi.org/10.3390/cells15050473

Cell Death Differ. 2026 Mar 14.

Ubiquitination of MEIS1 by MDM2 serves as a switch for p53 stabilization and DNA damage response activation.

Jiaxin Liu, Yanxia Duan, Qing Xiao, Shumin Deng, AiLin Li, Di Wu, Jingqiu Wu, Chang Liu, Hanxi Yi, Maonan Wang, Guang Shu, Gang Yin.

Targeting MDM2 by disrupting its interaction with p53 or inhibiting its E3 ligase activity is a promising strategy to restore p53 functionality. However, achieving anticancer efficacy while minimizing dose-limiting toxicities remains a significant challenge. Moreover, MDM2 also ubiquitinates various non-p53 targets, complicating its therapeutic targeting. In this study, we demonstrate that MDM2 directly facilitates K48-linked polyubiquitination of MEIS1 at K178, leading to its proteasomal degradation. Notably, MEIS1 forms a non-competitive ternary complex with MDM2 and p53, effectively promoting ubiquitin transfer to itself and preventing p53 ubiquitination. The MEIS1 K178R mutant, which is deficient in ubiquitination, fails to suppress MDM2-mediated p53 ubiquitination, demonstrating a mechanistic link between MEIS1 self-ubiquitination and p53 stabilization. Furthermore, MDM2-mediated MEIS1 ubiquitination is a prerequisite for p53 activation in the DNA damage response. Importantly, a MEIS1-derived peptide, which mimics the MDM2-mediating ubiquitination motif, enhances both MEIS1 and p53 stability, suppresses cell proliferation and tumor growth. Collectively, our findings identify MEIS1 as a molecular decoy that competes for ubiquitin transfer to protect p53 and highlight that MEIS1 ubiquitination could be a novel therapeutic target for reactivating p53-dependent tumor suppression.

DOI: https://doi.org/10.1038/s41418-026-01714-9

Cancer Res. 2026 Mar 11.

Targeting the Non-Homologous End-Joining Pathway Sensitizes MDM2-Amplified Liposarcoma to Doxorubicin by Enhancing p53-Mediated Senescence.

Thijs Jalving, Carine Dufau, Juan Simon Nieto, Daniela M D'Empaire Altimari, Susan E van Hal-van Veen, Elisabeth H Jin, Nils L Visser, Hester H Van Boven, Winette T A van der Graaf, Winan J van Houdt, Daniel S Peeper.

Dedifferentiated liposarcoma (DDLPS) is a rare cancer defined by amplification of MDM2 and CDK4. Conventional chemotherapy (doxorubicin) and targeted inhibition of MDM2 and CDK4 show sporadic responses, but most tumors display primary resistance. Here, we used an unbiased approach to identify therapeutic strategies sensitizing to these DDLPS therapies. Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor) or doxorubicin. Top screen hits were validated and characterized in both in vitro and in vivo models, while clinical data were used to corroborate molecular findings. Inactivation of genes related to G1/S transition (CDK2, CKS1B, E2F3 and CCNE1) and non-homologous end-joining (NHEJ; TDP2, PRKDC and XRCC4), enhanced sensitivity to palbociclib and doxorubicin, respectively. Genetic perturbation of TDP2 or pharmacological inhibition of DNA-PKcs using peposertib synergized with prolonged administration of low-dose doxorubicin to induce cell cycle arrest and senescence, and subsequent senolytic treatment with Bcl2 inhibitor navitoclax triggered senescent cells to undergo apoptosis. Despite the amplification of MDM2, senescence was mediated by p53. Consistently, TCGA and DepMap data suggested p53 activity in DDLPS. These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of low-dose doxorubicin in DDLPS, highlighting a potential therapeutic strategy exploiting p53-mediated cell cycle arrest and senescence. Furthermore, this study provides evidence of maintained baseline p53 activity in MDM2-amplified DDLPS.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1858