bims-midomi 2026-03-29 papers

Genes (Basel). 2026 Feb 26. pii: 270. [Epub ahead of print]17(3):

The Regulation of p53 by Ubiquitination and Implications for Therapeutic Targeting in Colorectal Cancer.

Background: The turnaround of the tumor suppressor p53 protein, the guardian of the genome, is closely regulated to ensure avoidance of its untimely activation, which could lead to the demise of normal cells. Cancer cells often display mutations in the gene TP53 encoding for p53, which interferes with its normal function. Methods: The genomic series of colorectal cancer from the Cancer Genome Atlas (TCGA) was interrogated to discover genomic alterations and determine the mRNA expression of enzymes affecting p53 ubiquitination in colorectal cancers with wild-type and mutant TP53. Results: Genomic alterations of p53-regulating E3 ubiquitin ligases were uncommon in colorectal cancers, the most frequent being mutations in RCHY1. Several p53-regulating E3 ligases were well expressed in subsets of colorectal cancers, two of which, MDM2 and TRIM24, displayed higher mRNA expressions than the normal colorectal epithelia. The former was particularly upregulated in TP53 wild-type colorectal cancers, and the latter was upregulated in both wild-type and mutant TP53 cancers. Upregulation of TRIM24 in TP53 mutant cancers was observed independently of the type of mutations (gain-of-function or other). Among E3 ligases used in proteolysis-targeting chimeras (PROTACs), VHL was upregulated together with its E2-conjugating enzyme UBE2S in colorectal cancers. Conclusions: This survey of p53-targeting ubiquitin ligases provides a roadmap for potential therapeutic strategies working by promoting the destruction of the mutant protein or reactivating its normal function in TP53-mutated colorectal cancers and promoting p53 function by preventing degradation in TP53 wild-type cancers.

Keywords: gain-of-function; proteolysis targeting chimeras; ubiquitin conjugating enzymes; ubiquitin ligases; ubiquitination

DOI: https://doi.org/10.3390/genes17030270

Vasc Health Risk Manag. 2026 ;22 596709

Dual Left Atrial Masses Causing Inflow Obstruction: A Rare Presentation of Primary Cardiac Intimal Sarcoma.

Xian Zhang, Yuejian Zhuo, Dongdong Zhang.

Aim: Primary cardiac intimal sarcoma is a rare entity with a poor prognosis, often requiring distinction from other undifferentiated cardiac sarcomas.
Case Presentation: A 55-year-old female presented with symptoms of heart failure. Imaging identified dual left atrial masses compromising mitral inflow and pulmonary venous return. Surgical excision was performed, and morphological analysis revealed a high-grade spindle cell sarcoma. Crucially, the diagnostic dilemma was resolved through molecular testing; immunohistochemistry showed diffuse overexpression of MDM2 and CDK4, and fluorescence in situ hybridization (FISH) confirmed the amplification of the MDM2 and CDK4 loci.
Conclusion: This case illustrates the diagnostic utility of MDM2 and CDK4 as specific biomarkers for cardiac intimal sarcoma. It reinforces the necessity of a multidisciplinary approach involving advanced molecular pathology to ensure accurate classification and appropriate management of rare cardiac malignancies.

Keywords: CDK4; MDM2 amplification; left atrial mass; primary cardiac intimal sarcoma; rare cardiac malignancies

DOI: https://doi.org/10.2147/VHRM.S596709

Pharmaceuticals (Basel). 2026 Mar 13. pii: 476. [Epub ahead of print]19(3):

The MDM2-p53 Axis in Osteosarcoma: Current Understanding of Regulatory Mechanisms and Targeted Therapeutic Strategies.

Wenxia Deng, Songyan Gao, Lige Yan, Qiuju Su, Si Chen.

Osteosarcoma, the most prevalent primary malignant bone tumor in children and adolescents, is characterized by high rates of metastasis, recurrence, and chemotherapy resistance, leading to suboptimal patient survival. The MDM2-p53 pathway plays a pivotal role in its tumorigenesis and progression, where dysregulation leads to loss of p53 function. This review systematically elucidates the molecular mechanisms of this pathway and summarizes diverse targeted therapeutic strategies, including small-molecule MDM2 inhibitors, mutant p53 reactivators, and innovative modalities such as gene therapy and Proteolysis Targeting Chimeras (PROTACs). Despite demonstrating potent preclinical activity with low IC50 values, the clinical translation of these agents has faced significant challenges. Early-generation MDM2 inhibitors (e.g., RG7112, Idasanutlin) showed limited monotherapy efficacy and dose-limiting toxicities like thrombocytopenia, halting their development at early-phase clinical trials. In contrast, novel MDM2 inhibitors like APG-115 have advanced to Phase II trials, marking a significant breakthrough. Although not yet tested in dedicated osteosarcoma cohorts, their safety and efficacy in MDM2-amplified solid tumors provide a critical foundation for the development of precision medicine and combination regimens for osteosarcoma. Future efforts to accelerate drug development may leverage single-cell sequencing and AI-aided drug design to decipher osteosarcoma heterogeneity and optimize drug profiles for reduced toxicity.

Keywords: MDM2-p53; drug resistance; osteosarcoma; targeted therapy

DOI: https://doi.org/10.3390/ph19030476

Cytotechnology. 2026 Apr;78(2): 69

Competitive binding of EGR1 to MDM2 causes P53 to promote high glucose-induced impairment of Schwann cell function.

Ya Ning, Yuewei Liang, Youqing Huang.

Background: Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus (DM). Schwann cells (SCs) dysfunction plays an important role in the pathogenesis of DNP. Early growth response protein 1 (EGR1) is related to apoptosis and immune regulation and plays important roles in neuropathic pain. However, its exact role in DNP-induced SCs injury is still unclear. Methods: A DNP mouse model was established using a high-fat diet combined with STZ, and a high glucose (HG)-induced RSC96 cell model was used for the experimental studies. The metabolic status of the mice was assessed by fasting blood glucose (FBG) levels. Pathological damage to the sciatic nerve was detected by HE staining. Pain sensitivity was comprehensively evaluated by the von Frey test and hot plate test. Cell viability was determined by a CCK-8 assay, and apoptosis was detected by TUNEL staining. Western blotting, immunohistochemistry, immunofluorescence, and ELISA were used to detect the expression of related proteins. Results: EGR1 was highly expressed in DNP mice and HG-induced RSC96 cells. Knockdown of EGR1 alleviated the symptoms of DNP mice, including a reduction in FBG levels, an increase in the tactile response threshold, a reduction in thermal response delay, and alleviation of sciatic nerve injury. In addition, EGR1 knockdown inhibited the apoptosis of SCs and inflammatory responses. In terms of molecular mechanisms, EGR1 competitively binds to MDM2 to inhibit MDM2-mediated P53 ubiquitination and increase P53 expression, thereby promoting HG-induced SC injury, whereas inhibition of MDM2 reverses the protective effect of EGR1 knockdown on SCs. Conclusion: EGR1 inhibits MDM2-mediated P53 ubiquitination and degradation by competitively binding to MDM2, resulting in the upregulation of P53 expression, thereby promoting HG-induced SC function injury and inflammatory responses and aggravating DNP.
Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-026-00935-7.

Keywords: Diabetic neuropathic pain; EGR1; MDM2; P53; Schwann cells

DOI: https://doi.org/10.1007/s10616-026-00935-7