bims-midomi 2025-06-01 papers

Biomolecules. 2025 Apr 30. pii: 642. [Epub ahead of print]15(5):

Mechanistic Role of the Mdm2/MdmX Lid Domain in Regulating Their Interactions with p53.

Qiuyin Wei, Chenqi Li, Yibing Tang, Jinping Bai, Wang Li, Jidong Liu, Zhengding Su, Xiyao Cheng.

p53 functions as a critical guardian of the genome, orchestrating tumor suppression pathways and ensuring the integrity of chromosomal stability. Mdm2 and MdmX, homologous proteins, serve as negative feedback regulators of p53. In approximately half of tumor cases, overexpression of Mdm2/MdmX results in the inhibition of p53 activity. Current research focuses on designing Mdm2 and MdmX inhibitors based on the structure of lidless N-terminal forms of these proteins. However, growing evidence suggests that the lid of Mdm2 and MdmX plays a key role in the selective binding of p53 and inhibitors. Therefore, targeting the lid in the screening and design of Mdm2/MdmX inhibitors may offer a novel strategy for developing anti-cancer drugs. This review examines the impact of the Mdm2/MdmX lid on ligand binding, providing valuable insights for future research and guiding new approaches to the screening and design of innovative anti-cancer therapeutics.

Keywords: Lid; Mdm2; MdmX; tumor suppressor protein p53

DOI: https://doi.org/10.3390/biom15050642

Oncologist. 2025 May 08. pii: oyaf094. [Epub ahead of print]30(5):

MDM2 as a therapeutic target in advanced biliary tract cancers.

Kristen R Spencer, Gentry G King.

Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from cells in the bile ducts and gallbladder. The 5-year overall survival rate for all BTC stages combined is ~20%, and treatment options for patients with unresectable disease are limited, leaving an unmet clinical need. In recent years, significant efforts have been made to refine and implement targeted therapeutic approaches for patients with BTC. The adoption of early and comprehensive molecular profiling is crucial to identifying patients who may be candidates for effective targeted therapies. Characterization of the molecular landscape of BTCs led to the identification of murine double minute 2 homolog gene (MDM2) amplification across all BTC subtypes. The MDM2 protein is a critical negative regulator of p53 stabilization and activity that is an emerging actionable biomarker in BTCs. There are multiple therapeutic approaches that aim to target MDM2 activity, thereby restoring the intrinsic tumor suppressor function of p53 and halting oncogenesis. However, these have been limited by our evolving understanding of the role of MDM2 in BTC pathogenesis. Here, we offer a review of the current understanding of the role of MDM2 in BTC biology and its therapeutic implications.

Keywords: MDM2 amplification; MDM2-p53; biliary tract cancer; cholangiocarcinoma; gallbladder cancer; oncogene

DOI: https://doi.org/10.1093/oncolo/oyaf094

Cancers (Basel). 2025 May 08. pii: 1597. [Epub ahead of print]17(10):

The Central Role of Ribosomal Proteins in p53 Regulation.

Mikael S Lindström.

The tumor suppressor protein p53 prevents the malignant transformation of cells by responding to DNA damage, oncogene activation, and abnormal growth signals including ribosome assembly defects. Under normal conditions, p53 activity is controlled by the regulatory proteins MDM2 and MDM4, which suppress its function through ubiquitin-mediated degradation and transcriptional inhibition. A subset of ribosomal proteins initiates the p53 response to impaired ribosome biogenesis. The ability of some ribosomal proteins to control MDM2 and MDM4 activities, and thereby p53, underscores an intriguing aspect of cell biology: proteins primarily known for their roles in ribosome function can exert extra-ribosomal functions. One notable example is the cellular RNA-protein complex involving RPL5, RPL11, and 5S rRNA (5S RNP) which inhibits MDM2 and stabilizes p53. Another RP, RPL22, is frequently mutated in cancers with microsatellite instability and its paralog RPL22L1 is often amplified. Recent studies have revealed that RPL22 directly modulates the alternative splicing of MDM4 to promote p53 activation, suggesting that the ribosomal protein-p53 relationship is more complex than previously thought. Cellular responses to ribosome biogenesis inhibition extend beyond general alterations in transcription and translation to actively determine cancer cell fate by selectively engaging tumor-suppressor pathways. RPL22's effect on MDM4 and other mRNA splicing events is a striking example. A better understanding of the mechanisms involved could guide the development of improved cancer treatments.

Keywords: MDM2 inhibitors; MDM4; RPL22; alternative splicing; chemotherapy resistance; p53; ribosomal protein; ribosomal stress response; ribosome biogenesis

DOI: https://doi.org/10.3390/cancers17101597

Eur J Med Chem. 2025 May 21. pii: S0223-5234(25)00558-6. [Epub ahead of print]295 117793

Characterization of a dual degrader of MDM2 and GSPT1.

Ira Tandon, Paulina N Esguerra, Chunrong Li, Huan Sun, Ka Yang, Zhongrui Zhang, Junmin Peng, Weiping Tang.

Murine double minute 2 (MDM2) has long been a therapeutic target to stabilize and upregulate wild-type tumor protein 53 (p53) in cancer. We initially reported WB156 as a degrader of MDM2 that can upregulate p53 levels in acute leukemia. To further evaluate the therapeutic potential of WB156, we tested it in a variety of cancers alongside another reported MDM2 degrader. We found that WB156 is active in wild-type and mutant p53-bearing leukemias due to its ability to degrade both MDM2 and G1 To S Phase Transition 1 (GSPT1) protein. In cancers that are non-responsive to MDM2 degradation alone, WB156 acts as a GSPT1 degrader to induce anti-proliferative effects. Here, we report the first MDM2/GSPT1 dual degrader that also upregulates p53 levels.

Keywords: Dual degrader; GSPT1; MDM2; PROTACs; p53

DOI: https://doi.org/10.1016/j.ejmech.2025.117793

Breast Cancer Res Treat. 2025 May 29.

Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes.

Arielle J Medford, Marko Velimirovic, Yifat Gefen, Andrzej Niemierko, Lorenzo Gerratana, Andrew A Davis, Katherine Clifton, Jennifer Keenan, Emily Podany, Whitney L Hensing, Carolina Reduzzi, Charles S Dai, Lesli A Kiedrowski, Laura M Spring, Leif W Ellisen, Robert C Doebele, Massimo Cristofanilli, Gad Getz, Aditya Bardia.

PURPOSE: GATA3 mutations are among the most common alterations in hormone receptor-positive (HR+) breast cancer (BC), yet these have no targeted therapies. MDM2 is an E3 ubiquitin ligase that targets p53 for degradation, and pre-clinical data suggests MDM2 inhibition may effectively treat GATA3mut HR+ BC. The GATA3 co-mutational landscape has been described only in primary BC tissue, and the mechanism of MDM2-driven efficacy is incompletely understood.
EXPERIMENTAL DESIGN: Circulating tumor DNA (ctDNA) was assessed for GATA3 mutations via targeted sequencing. Associations with co-alterations and clinical/pathologic factors were estimated using Pearson's chi-squared test, two-sample Wilcoxon rank-sum, and multivariable logistic regression. Impact on survival was analyzed using multivariable Cox regression analysis. Tissue-based data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database was evaluated for expression and phosphorylation of GATA3 and associated proteins.
RESULTS: Among 609 patients with HR + /HER2- MBC, ctDNA detected non-synonymous GATA3 variants ctDNA in 69 (11%) patients, and the genomic landscape was unique from tissue-based primary BC data; GATA3mut were not mutually exclusive from TP53mut (p = 0.30) or PIK3CAmut (p = 0.52) and were associated with poorer survival on endocrine monotherapy. CPTAC analysis showed no difference in GATA3 or breast cancer-associated gene abundance, however there was increased USP48 (LogFC = 0.76, FDR = 1.7 × 10-5), which stabilizes MDM2.
CONCLUSION: The distinct landscape in GATA3mut MBC ctDNA highlights critical information when assessing candidacy for targeted therapies. To our knowledge, this is the first ctDNA-based GATA3mut landscape analysis in MBC. Furthermore, tissue-based proteomic analysis suggests mechanisms for endocrine resistance and sensitivity to MDM2 inhibition in HR+ /HER2- GATA3mut BC.

Keywords: Breast cancer; Circulating tumor DNA; Genomics; Liquid biopsy

DOI: https://doi.org/10.1007/s10549-025-07710-w

J Cell Mol Med. 2025 May;29(10): e70627

The Impact of METTL3 on MDM2 Promotes Podocytes Injury During Diabetic Kidney Disease.

Han Wu, Ziyang Yu, Yitian Yang, Zhuoting Han, Qingjun Pan, Ying Chen, Hongyuan Yu, Siman Shen, Li Xu.

N6-Methyladenosine (m6A) methylation plays a role in various pathological processes, including renal fibrosis and aging. Our previous studies have highlighted abnormal expression of the methyltransferase enzyme, methyltransferase like 3 (METTL3), in aging kidney tissues. This study aims to elucidate the regulatory mechanisms of METTL3 in diabetic kidney disease (DKD) by establishing a conditional METTL3 knockout model. We observed elevated m6A levels in the kidneys of type I diabetic mice and in cultured mouse podocytes exposed to advanced glycation end products (AGEs). These increases were attributed to enhanced METTL3 expression. Significantly, podocyte-specific METTL3 knockdown mitigated injury in streptozotocin (STZ)-induced diabetic mice, evidenced by reduced urine albuminuria and renal pathology. We discovered that METTL3 induced abnormal m6A modification of murine double minute 2 (MDM2), which triggered its degradation in an IGF2BP2 (insulin-like growth factor 2 mRNA-binding protein 2)-dependent manner. This modification led to increased MDM2 expression, activating the Notch signalling pathway and inducing podocyte cell cycle arrest under diabetic conditions, which further released inflammatory factors and caused podocyte dedifferentiation. Our findings suggest that targeting m6A modification via METTL3 could be an effective strategy for treating DKD.

Keywords: N6‐Methyladenosine; dedifferentiation; diabetic kidney disease; murine double minute 2; podocytes

DOI: https://doi.org/10.1111/jcmm.70627