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We have shown previously that phosphorylation of Mdm2 by ATM and c-Abl regulates Mdm2-p53 signaling and alters the effects of DNA damage in mice, including bone marrow failure and tumorigenesis induced by ionizing radiation. Here, we examine the physiological effects of Mdm2 phosphorylation by Akt, another DNA damage effector kinase. Surprisingly, Akt phosphorylation of Mdm2 does not alter the p53-mediated effects of ionizing radiation in cells or mice but regulates the p53 response to oxidative stress. Akt phosphorylation of Mdm2 serine residue 183 increases nuclear Mdm2 stability, decreases p53 levels, and prevents senescence in primary cells exposed to reactive oxidative species (ROS). Using multiple mouse models of ROS-induced cancer, we show that Mdm2 phosphorylation by Akt reduces senescence to promote KrasG12D-driven lung cancers and carcinogen-induced papilloma and hepatocellular carcinomas. Collectively, we document a unique physiologic role for Akt-Mdm2-p53 signaling in regulating cell growth and tumorigenesis in response to oxidative stress.

The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed.

Although most cases of Burkitt lymphoma (BL) respond well to chemotherapy, relapsed or refractory BL, particularly in the presence of TP53 aberrations, presents a significant therapeutic challenge. TP53 germline or mosaic mutations, though rare, are clinically relevant in lymphomas as they persist in both lymphoma cells and autologous chimeric antigen receptor (CAR)‐T cells, potentially influencing treatment outcomes. Here, we report the first documented case of a TP53 mosaic mutation and a 17p deletion in an adult patient with refractory BL. After four cycles of unsuccessful standard induction chemotherapy, the patient received CAR‐T cell therapy combined with autologous stem cell transplantation. The comprehensive treatment plan included radiotherapy bridging, sequential infusions of CD19 and CD22 CAR‐T cells, and maintenance therapy with chidamide, obinutuzumab, sintilimab, and azacitidine. Two months postinfusion, the patient achieved complete remission, which has been sustained for 24 months to date. This case indicates that, despite the challenges posed by multiple‐hit TP53 aberrations in refractory BL, a multifaceted therapeutic approach can achieve positive outcomes. Furthermore, based on previous studies and our findings, we speculate that TP53 alterations may play a biphasic role in this patient's CAR‐T therapy: in lymphoma cells, TP53 alterations impair CAR‐T cell cytotoxicity, while in CAR‐T cells, they may promote enhanced expansion and persistence. This potential dual role might help explain why TP53 deficiency does not universally affect the efficacy of CAR‐T therapy in certain studies.

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRAS G12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRAS G12C -driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRAS G12C , efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRAS G12C signaling increases autophagy in KRAS G12C -expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRAS G12C -driven lung cancer cell proliferation in vitro and superior tumor control in vivo. Additionally, in genetically engineered mouse models of KRAS G12C -driven NSCLC, inhibition of either KRAS G12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRAS G12C in lung cancer.

The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.

The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53.

The tumour suppressor protein p53 plays a central role in safeguarding genomic integrity through the regulation of DNA repair, cell cycle arrest, and apoptosis. Mutations in TP53, particularly within its DNA-binding domain, are among the most frequent genetic alterations in human cancers and are strongly associated with chemoresistance and poor prognosis. In this study, all TP53 mutations reported in the COSMIC database were systematically mapped onto all experimentally resolved TP53 three-dimensional structures available in the Protein Data Bank, supplemented with AlphaFold-predicted models to achieve full structural coverage. Mutations were classified according to their structural context—protein core, interface regions, ligand- and zinc-binding sites, and intrinsically disordered regions—and evaluated using complementary sequence- and structure-based predictive tools. The analysis revealed distinct mutational hotspots, differential distribution across structural regions, and context-dependent effects on stability and DNA-binding capacity. Notably, a subset of mutations exhibited consistent predictions of high destabilisation across all structural contexts, underscoring their potential as drivers of functional inactivation. By providing a comprehensive structural map of TP53 alterations, this work offers a valuable resource for understanding mutation-specific mechanisms of p53 dysfunction and for guiding the development of precision therapeutic strategies aimed at restoring its tumour-suppressive functions.

Li–Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by germline pathogenic variants in the TP53 gene. With the increasing use of multi‐gene panel testing, TP53 variants have been identified in individuals who do not meet established TP53 testing criteria, such as the Chompret criteria. The term “attenuated LFS” has been proposed for some of these cases, particularly those with adult‐onset cancer. We analyzed participants of the Japanese nationwide prospective clinical trial of the cancer surveillance program (Japan Children's Cancer Group LFS‐20), along with clinical information including their family histories, to better understand their genotypic and phenotypic characteristics. We identified 32 distinct TP53 variants from 41 families (45 participants), including four missense variants with conflicting classifications of pathogenicity in ClinVar. Among these families, 36 (88%) met the LFS criteria (hereafter referred to as “LFS” in contrast to attenuated LFS), while 5 (12%) were classified as attenuated LFS. Including 30 additional family members carrying the same variant, we analyzed 75 individuals with TP53 variants. Of these, 40 with LFS and 6 with attenuated LFS had cancer. Multiple primary cancers occurred in 22 individuals (21 LFS, 1 attenuated LFS). LFS‐core tumors accounted for 66% (58/88) of cancers in the LFS group and 63% (5/8) in the attenuated LFS group; of note, all core tumors in the attenuated group were limited to breast cancer. Hotspot missense variants were detected in 11 of 36 LFS families and in none of 5 attenuated LFS families, and non‐hotspot null variants were found in 14 and 1, respectively. Our study revealed genotype–phenotype correlations in several respects. UMIN‐CTR: UMIN000045855.

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including ‘apoptosis’, ‘necrosis’ and ‘mitotic catastrophe’. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.