Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes

Redman, Lindsay N.; Shaver, Timothy M.; Jin, Hailing; Marshall, Clayton B.; Schafer, Johanna M.; Sheng, Quanhu; Hongo, Rachel; Beckermann, Kathryn E.; Wheeler, Ferrin C.; Lehmann, Brian D.; Pietenpol, Jennifer A.

doi:10.1038/s41467-021-25359-z

Cited by 37 publications

(31 citation statements)

References 102 publications

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“…We did not observe mtp53 R273H mediated transactivation of either CDC7 or RRM2 ( Supplementary Figure S2 ). This supports the recent finding that outcomes on activation of new genes may result from aneuploidy and are not direct results of mtp53 R273H transactivation ( Redman-Rivera et al, 2021 ).…”

Section: Discussionsupporting

confidence: 91%

“…Exogenous expression of GOF mtp53 (R175H or R273H) in human cells correlates with the increased transcription of DNA replicating factor CDC7 (which increases DNA replication origin firing) ( Datta et al, 2017 ). The transcriptional activation of previously silent genes in the presence of mtp53 in cancer cells has recently been associated with p53 mutations driving aneuploidy, rather than as a direct transcriptional response ( Redman-Rivera et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Oligomerization of Mutant p53 R273H is not Required for Gain-of-Function Chromatin Associated Activities

Annor

Elshabassy

Lundine

et al. 2021

Front. Cell Dev. Biol.

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The TP53 gene is often mutated in cancer, with missense mutations found in the central DNA binding domain, and less often in the C-terminal oligomerization domain (OD). These types of mutations are found in patients with the rare inherited cancer predisposition disorder called Li-Fraumeni syndrome. We previously found that mutant p53 (mtp53) R273H associates with replicating DNA and promotes the chromatin association of replication-associated proteins mini-chromosome maintenance 2 (MCM2), and poly ADP-ribose polymerase 1(PARP1). Herein, we created dual mutants in order to test if the oligomerization state of mtp53 R273H played a role in chromatin binding oncogenic gain-of-function (GOF) activities. We used site-directed mutagenesis to introduce point mutations in the OD in wild-type p53 (wtp53), and mtp53 R273H expressing plasmids. The glutaraldehyde crosslinking assay revealed that both wtp53 and mtp53 R273H formed predominantly tetramers, while the single OD mutant A347D, and the dual mtp53 R273H-A347D, formed predominantly dimers. The R337C, L344P, mtp53 R273H-R337C, and mtp53 R273H-L344P proteins formed predominantly monomers. Wtp53 was able to activate the cyclin-dependent kinase gene p21/waf and the p53 feedback regulator MDM2. As expected, the transactivation activity was lost for all the single mutants, as well as the mtp53 R273H-dual mutants. Importantly, mtp53 R273H and the dual oligomerization mutants, R273H-A347D, R273H-R337C, and R273H-L344P were able to interact with chromatin. Additionally, the dual oligomerization mutants, R273H-A347D, R273H-R337C, and R273H-L344P, maintained strong interactions with MCM2 and PARP1. Our findings suggest that while mtp53 R273H can form tetramers, tetramer formation is not required for the GOF associated chromatin interactions.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Oligomerization of Mutant p53 R273H is not Required for Gain-of-Function Chromatin Associated Activities

Annor

Elshabassy

Lundine

et al. 2021

Front. Cell Dev. Biol.

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“…Differences in proliferation, colony formation, and metabolism are associated with aneuploidy but not mutant p53 expression. How the genomic changes that contribute to oncogenic gain-of-function (GOF) phenotypes after WT p53 is lost remains to be further studied [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

High expression of eIF4E is associated with tumor macrophage infiltration and leads to poor prognosis in breast cancer

Fan

Sun

et al. 2021

BMC Cancer

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Background The expression and activation of eukaryotic translation initiation factor 4E (eIF4E) is associated with cell transformation and tumor initiation, but the functional role and the mechanism whereby it drives immune cell infiltration in breast cancer (BRCA) remain uncertain. Methods Oncomine, Timer and UALCAN were used to analyze the expression of eIF4E in various cancers. PrognoScan, Kaplan–Meier plotter, and GEPIA were utilized to analyze the prognostic value of eIF4E in select cancers. In vitro cell experiments were used to verify the role of eIF4E in promoting the progression of BRCA. ImmuCellAI and TIMER database were used to explore the relationship between eIF4E and tumor infiltrating immune cells. The expression of a macrophage marker (CD68+) and an M2-type marker (CD163+) was evaluated using immunohistochemistry in 50 invasive BRCA samples on tissue microarrays. The Human Protein Atlas (HPA) database was used to show the expression of eIF4E and related immune markers. LinkedOmics and NetworkAnalyst were used to build the signaling network. Results Through multiple dataset mining, we found that the expression of eIF4E in BRCA was higher than that in normal tissues, and patients with increased eIF4E expression had poorer survival and a higher cumulative recurrence rate in BRCA. At the cellular level, BRCA cell migration and invasion were significantly inhibited after eIF4E expression was inhibited by siRNA. Immune infiltration analysis showed that the eIF4E expression level was significantly associated with the tumor purity and immune infiltration levels of different immune cells in BRCA. The results from immunohistochemical (IHC) staining further proved that the expression of CD68+ and CD163+ were significantly increased and correlated with poor prognosis in BRCA patients (P < 0.05). Finally, interaction network and functional enrichment analysis revealed that eIF4E was mainly involved in tumor-related pathways, including the cell adhesion molecule pathway and the JAK-STAT signaling pathway. Conclusions Our study has demonstrated that eIF4E expression has prognostic value for BRCA patients. eIF4E may act as an essential regulator of tumor macrophage infiltration and may participate in macrophage M2 polarization.

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“…Thus, our approach was not designed to dissect differences between these types of p53 alterations. However, recent studies have found that most of the GOF phenotypes thought to be directly mutant p53-mediated are, in fact, related primarily to the aneuploidy and genomic entropy caused by p53 LOF [ 33 ]. Secondly, we used pharmacologic selection with nutlin-3a (7 days) to select p53 LOF populations within our cell line models.…”

Section: Discussionmentioning

confidence: 99%

Combined Dusp4 and p53 loss with Dbf4 amplification drives tumorigenesis via cell cycle restriction and replication stress escape in breast cancer

et al. 2022

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Aim Deregulated signaling pathways are a hallmark feature of oncogenesis and driver of tumor progression. Dual specificity protein phosphatase 4 (DUSP4) is a critical negative regulator of the mitogen-activated protein kinase (MAPK) pathway and is often deleted or epigenetically silenced in tumors. DUSP4 alterations lead to hyperactivation of MAPK signaling in many cancers, including breast cancer, which often harbor mutations in cell cycle checkpoint genes, particularly in TP53. Methods Using a genetically engineered mouse model, we generated mammary-specific Dusp4-deleted primary epithelial cells to investigate the necessary conditions in which DUSP4 loss may drive breast cancer oncogenesis. Results We found that Dusp4 loss alone is insufficient in mediating tumorigenesis, but alternatively converges with loss in Trp53 and MYC amplification to induce tumorigenesis primarily through chromosome 5 amplification, which specifically upregulates Dbf4, a cell cycle gene that promotes cellular replication by mediating cell cycle checkpoint escape. Conclusions This study identifies a novel mechanism for breast tumorigenesis implicating Dusp4 loss and p53 mutations in cellular acquisition of Dbf4 upregulation as a driver of cellular replication and cell cycle checkpoint escape.

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Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes

Cited by 37 publications

References 102 publications

Oligomerization of Mutant p53 R273H is not Required for Gain-of-Function Chromatin Associated Activities

Oligomerization of Mutant p53 R273H is not Required for Gain-of-Function Chromatin Associated Activities

High expression of eIF4E is associated with tumor macrophage infiltration and leads to poor prognosis in breast cancer

Combined Dusp4 and p53 loss with Dbf4 amplification drives tumorigenesis via cell cycle restriction and replication stress escape in breast cancer

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