bims-midomi 2026-01-25 papers

Dev Comp Immunol. 2026 Jan 16. pii: S0145-305X(26)00010-8. [Epub ahead of print]176 105554

Characterizing p53 structural insights of variants in vertebrates that interfere its regulatory interaction with Mdm2.

Umesh Kalathiya, Natalia Marek-Trzonkowska, Monikaben Padariya.

The tumor suppressor p53, transcriptionally regulates several target genes, and in the absence of cellular stress its basal protein levels are tightly regulated by Mdm2 (Murine double minute 2). Species with functional p53 are less prone to cancer, and in mammals this oncogene has a multifunctional role towards cancer tolerance. Herein, we examined naturally evolving p53 protein across vertebrates with its negative regulator, along with exploring their structural properties. Several mammalian species contain conserved p53 amphipathic α-helical BOX-I, DNA-binding domain (DBD), and basic domains, whereas Loxodonta africana (elephant) exhibits the lowest sequence similarities. Vertebrates with notable insertion in the DBD or disordered BOX-I regions gained a unique structural orientation, that can potentiate to escape Mdm2 negative regulation. Comprehending molecular details, we constructed an Mdm2 pharmacophore model that can interact with a specific set of p53 isoforms. To explore potential use of BOX-I derived linear motifs as peptidomimetic molecules targeting Mdm2 we assessed their binding affinity, as well as the effect of temperature over the p53-Mdm2 complex. Conformational changes adopted by p53 variants identify crucial residues within the FxxxW/GxxL motif. These residues face the Mdm2 pocket and may enhance binding affinity, even under thermal change. Mdm2 was found mutated heavily in carcinoma, and its variant can have a significant role when associating with p53. Our findings demonstrate a natural living model, to utterly contribute to the mechanistic understanding of the role of p53 in its activation, giving insight on structural properties aiming to target these biomarkers in cancer therapeutics.

Keywords: Cancer; Mdm2; Negative regulator; Peptidomimetics; Thermal effect; Tumor suppressor; p53

DOI: https://doi.org/10.1016/j.dci.2026.105554

Arch Biochem Biophys. 2026 Jan 17. pii: S0003-9861(26)00004-4. [Epub ahead of print]778 110733

USP15 promotes proliferation, migration, and apoptosis resistance of pulmonary arterial smooth muscle cells by targeting MDM2.

Yanan Qi, Qixing Dong, Ping Luo, Jiaxin Meng, Beiping Guo, Xianglu Zhang, Leining Shan, Minyi Fu, Lizhen Yang, Jun Peng, Bin Liu.

BACKGROUND: Pulmonary vascular remodeling is the core pathological feature of pulmonary arterial hypertension (PAH). This process involves intricate changes in pulmonary arterial smooth muscle cells (PASMC), such as proliferation, migration, and resistance to apoptosis. Recent in-depth research has uncovered that ubiquitination or deubiquitination may play a vital role in pulmonary vascular remodeling by regulating the stability of substrate proteins and nuclear localization. The development of drugs targeting ubiquitination or deubiquitination enzymes may offer new strategies for preventing and treating PAH.
METHODS AND RESULTS: We initially identified deubiquitinase-related genes that were differentially expressed in the lung tissues of PAH patients using the GEO database. These findings were then validated in two classic PAH rat models induced by MCT or SuHx. Our experimental results revealed a significant increase in the expression of USP15 in both models, particularly in the pulmonary vascular smooth muscle layer. Furthermore, we observed that in our PDGF-BB or hypoxia-induced PASMC model studies, the proliferation, migration, and apoptotic resistance of PASMC induced by PDGF-BB or hypoxia were effectively inhibited by USP15 siRNA. Subsequent mechanism studies demonstrated that silencing USP15 prevented the up-regulation of murine double minute 2 (MDM2) in PASMC induced by PDGF-BB or hypoxia. Conversely, the overexpression of USP15 facilitated proliferation, migration, and apoptosis resistance in PASMC, which was associated with the increased expression of MDM2.
CONCLUSIONS: USP15 may facilitate the proliferation, migration, and apoptosis resistance of PASMC by targeting MDM2 expression and ultimately participating in pulmonary vascular remodeling. Therefore, the USP15/MDM2 pathway could be a potential therapeutic target for preventing pulmonary vascular remodeling.

Keywords: And apoptotic resistance; Migration; Murine double minute 2; Proliferation; Pulmonary arterial hypertension; Pulmonary arterial smooth muscle cells; Pulmonary vascular remodeling; Ubiquitin-specific proteases 15

DOI: https://doi.org/10.1016/j.abb.2026.110733

Research (Wash D C). 2026 ;9 1086

ARTS Confers Chemoresistance of Breast Cancer by Inducing Apoptosis-Dependent Autophagy via Livin-MDM2-p53 Pathway.

Hao Wang, Qianying Guo, Yuting Shen, Keshuo Ding, Yinfeng Chen, Xiaonan Wang, Xing Huang, Zhengsheng Wu.

Apoptosis and autophagy are fundamental pathophysiological programs governing cell fate decisions under stress, particularly during anticancer therapy. However, the interplay between apoptosis and autophagy in cancer chemoresistance remains incompletely understood. Here, we identify the apoptosis-related protein in the transforming growth factor-β signaling pathway (ARTS) as a key molecular transferring apoptotic signal to autophagic machinery to promote cell survival and chemoresistance. ARTS was highly expressed in chemoresistant breast cancer tissues and was associated with poor patient prognosis. ARTS conferred resistance to doxorubicin and docetaxel by inducing protective autophagy in vitro and in vivo cancer models. Mechanistically, upon proapoptotic signaling triggered by chemotherapeutic agents, ARTS translocated from the mitochondrial intermembrane space into the cytosol, where it induced autophagy through triggering seven in absentia homolog 1-mediated degradation of Livin and subsequent engagement of the mouse double minute 2 homolog (MDM2)-p53 axis, thereby promoting cancer cell survival. Pharmacologic inhibition of caspases or autophagic flux attenuated ARTS-mediated chemoresistance. Overall, this study delineates an apoptosis-dependent ARTS-Livin-MDM2-p53 pathway that drives autophagy and confers chemoresistance in breast cancer.

DOI: https://doi.org/10.34133/research.1086