bims-midomi 2026-05-24 papers

Clin Transl Oncol. 2026 May 20.

Role of the MDM2/p53 axis in regulating cisplatin response in tumor cells.

Yasamin Rajabloo, Iman Akhlaghipour, Negin Taghehchian, Meysam Moghbeli.

Cisplatin remains a cornerstone chemotherapeutic agent for a broad spectrum of solid malignancies; however, the emergence of intrinsic and acquired resistance severely limits its clinical efficacy. Central to the cellular decision between DNA damage repair and apoptosis following cisplatin exposure is the tumor suppressor p53, whose function is tightly governed by its primary negative regulator, Murine Double Minute 2 (MDM2). This review provides a critical synthesis of the molecular interplay within the MDM2/p53 axis and its direct impact on cisplatin sensitivity. We discussed how deregulation of this axis via TP53 mutational inactivation or MDM2 overexpression enables tumor cells to tolerate cisplatin-induced genotoxic stress. Specifically, we analyzed the dual role of MDM2: its E3 ubiquitin ligase activity that targets p53 for proteasomal degradation, and its emerging p53-independent functions in promoting DNA repair fidelity. Furthermore, we evaluated the therapeutic implications of targeting this pathway with small-molecule MDM2 antagonists. We assessed preclinical and clinical evidence supporting the use of MDM2 inhibition to lower the apoptotic threshold and re-sensitize resistant tumors to cisplatin. Therefore, an understanding of the MDM2/p53 feedback loop is essential for optimizing cisplatin-based regimens and developing rational combination therapies to circumvent chemoresistance.

Keywords: Chemoresistance; Cisplatin; MDM2; Prognosis; p53

DOI: https://doi.org/10.1007/s12094-026-04389-3

Cell Death Discov. 2026 May 22.

USP21 functions as an oncogenic regulator of the Mdm2-p53 axis in colorectal cancer.

Zhongyu Wang, Bo Yao, Weiran He, Xiaorui Guo, Ning Yu, Suyun Tang, Linzhu Luo, Fang Wang, Kailiang Zhao, Yide Mei.

The tumor suppressor p53 is a pivotal guardian against tumorigenesis, with its activity primarily constrained by the ubiquitin E3 ligase Mdm2. However, the full complexity of the Mdm2-p53 regulatory network remains elusive. Here we report that the deubiquitinating enzyme USP21 physically interacts with and stabilizes Mdm2 in a deubiquitinase activity-independent manner. Mechanistically, USP21 acts as a scaffold to facilitate the USP7-Mdm2 interaction, enhancing Mdm2 stability and consequently promoting p53 ubiquitination and degradation. Functionally, USP21-mediated p53 suppression attenuates its tumor suppressive activity and accelerates colorectal cancer progression. Clinically, USP21 is upregulated in colorectal cancer tissues, and its elevated expression correlates with poor overall survival in patients with wild-type p53 tumors, but not in those with p53 mutations. These findings establish USP21 as an important regulator of the Mdm2-p53 axis and reveal its critical role in promoting colorectal carcinogenesis via p53 inhibition.

DOI: https://doi.org/10.1038/s41420-026-03170-3

Mol Cancer Res. 2026 May 18.

Variation at the R181 residue of p53 confers loss of p53 DNA binding cooperativity with the retention of mitochondrial-associated apoptosis.

Renyta Moses, Alexandra Indeglia, Alison S Levine, Ryan Hausler, Gregory Kelly, Sven A Miller, Isabel Anez, Melissa Heller, Rosella Delgado, Caitlin Orr, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Sophie R Cahill, Luke D Maese, John Karanicolas, Judy E Garber, Maureen E Murphy, Kara N Maxwell.

The p53 tumor suppressor binds DNA cooperatively as a tetramer, mediated by salt-bridge interactions between p53 residues E180 and R181 from two different p53 monomers. Variants at the R181 residue are one of the most identified TP53 pathogenic variants by germline genetic testing. We show that families with TP53 p.R181H and p.R181C variants have an attenuated cancer risk phenotype compared to patients with hotspot dominant negative loss of function TP53 variants. Despite this phenotype, we find that p53 R181H and R181C variants have significantly reduced ability to bind to p53 promoter/enhancer target sequences and transactivate p53 target genes, similar to null variants. However, p53 R181H and R181C retain wild-type p53 structure and tetramerization. In addition, R181-mutant cells undergo apoptosis through wild-type p53 activity at the mitochondria. These results suggest that retention of transcription-independent p53 tumor suppressor function results in a reduced penetrance cancer risk syndrome in humans. Implications: We report the first separation of function DNA binding domain p53 mutation that results in retention of transcription-independent p53 functions despite loss of p53 transactivation activity, resulting in a reduced penetrance phenotype.

DOI: https://doi.org/10.1158/1541-7786.MCR-26-0030