Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells

Allende-Vega, Nerea; Villalba, Martín

doi:10.1038/s41598-019-42220-y

Cited by 22 publications

(33 citation statements)

References 51 publications

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“…It should be noted here that U937 and HL60 are p53 null cell lines and hence, the green fluorescence emitted is completely from the interaction between green anti-p53 and PNC-27 (DO-1 anti-p53 binds to PNC-27, a peptide construct derived from p53) on the cell surface. Furthermore, even though OCI-AML3 has wildtype p53, p53 is not stable at the protein level and expresses no significant levels of p53 protein (14). Hence, we can conclude that the green fluorescence in OCI-AML3 cells is a result of PNC-27 localized at the cell membrane.…”

Section: Pnc-27 Binds To Membrane Hdm-2 In Vitromentioning

confidence: 84%

Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells

et al. 2020

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Background/Aim: Anticancer peptide PNC-27 binds to HDM-2 protein on cancer cell membranes inducing the formation of cytotoxic transmembrane pores. Herein, we investigated HDM-2 membrane expression and the effect of PNC-27 treatment on human non-stem cell acute myelogenous leukemia cell lines: U937, acute monocytic leukemia; OCI-AML3, acute myelomonocytic leukemia and HL60, acute promyelocytic leukemia. Materials and Methods: We measured cell surface membrane expression of HDM-2 using flow cytometry. Cell viability was assessed using MTT assay while direct cytotoxicity was measured by lactate dehydrogenase (LDH) release and induction of apoptotic markers annexin V and caspase-3. Results: HDM-2 is expressed at high levels in membranes of U937, OCI-AML3 and HL-60 cells. PNC-27 can bind to membrane HDM-2 to induce cell necrosis and LDH release within 4 h. Conclusion: Targeting membrane HDM-2 can be a potential strategy to treat leukemia. PNC-27 targeting membrane HDM-2 demonstrated significant anti-leukemia activity in a variety of leukemic cell lines.

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Section: Pnc-27 Binds To Membrane Hdm-2 In Vitromentioning

confidence: 84%

Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells

et al. 2020

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“…As these cell lines express p53 in varying degrees, we show the importance of titrating antibodies on relevant samples. HL60 cells do not express full-length p53 due to deletion in both alleles [ 39 ], while NB4 cells carry a TP53 mutation, which results in high protein expression [ 40 ]. An antibody concentration titrated correctly for MOLM13 and HL60 cells might therefore not be the ideal concentration for NB4 cells.…”

Section: Discussionmentioning

confidence: 99%

Single Cell Detection of the p53 Protein by Mass Cytometry

Fagerholt

Hellesøy

Gullaksen

et al. 2020

Cancers

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Purpose: The p53 protein and its post-translational modifications are distinctly expressed in various normal cell types and malignant cells and are usually detected by immunohistochemistry and flow cytometry in contemporary diagnostics. Here, we describe an approach for simultaneous multiparameter detection of p53, its post-translational modifications and p53 pathway-related signaling proteins in single cells using mass cytometry. Method: We conjugated p53-specific antibodies to metal tags for detection by mass cytometry, allowing the detection of proteins and their post-translational modifications in single cells. We provide an overview of the antibody validation process using relevant biological controls, including cell lines treated in vitro with a stimulus (irradiation) known to induce changes in the expression level of p53. Finally, we present the potential of the method through investigation of primary samples from leukemia patients with distinct TP53 mutational status. Results: The p53 protein can be detected in cell lines and in primary samples by mass cytometry. By combining antibodies for p53-related signaling proteins with a surface marker panel, we show that mass cytometry can be used to decipher the single cell p53 signaling pathway in heterogeneous patient samples. Conclusion: Single cell profiling by mass cytometry allows the investigation of the p53 functionality through examination of relevant downstream signaling proteins in normal and malignant cells. Our work illustrates a novel approach for single cell profiling of p53.

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“…In line with this, glucose restriction in multiple cancer types bearing the p53 R175H, R280K mutants was shown to induce p53 mutant deacetylation, routing it for degradation via MA ( 158 ) ( Figure 3 ). Accordingly, several studies now demonstrate that lysosomes indeed represent a degradation route for certain mutant p53 proteins ( 159 – 161 ). MA inhibition by either chemical inhibitors or downregulation of key autophagic related genes ( ULK1 , BCN1 or ATG5 ) induce stabilization of mutant p53, while, the overexpression of Ulk1 or Beclin-1 results in mutant p53 degradation ( 162 ).…”

Section: Mutant P53 As Target Of Autophagymentioning

confidence: 99%

“…Nonetheless, the discovery that mutant p53 proteins are CMA substrates provided experimental evidence that CMA could be exploited as a novel approach to eliminate mutant p53 in cancer cells. Accumulating evidence now support that CMA activation plays a role in mutant p53 targeting ( 161 ). In fact, beyond mutant p53, CMA has been shown to promote the degradation of other oncoproteins, as HK2 and c-Myc ( 66 , 67 ).…”

Section: Mutant P53 As Target Of Autophagymentioning

confidence: 99%

Mutant p53 as a Regulator and Target of Autophagy

Shi

Norberg

Vakifahmetoglu-Norberg

2021

Front. Oncol.

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One of the most notoriously altered genes in human cancer is the tumor-suppressor TP53, which is mutated with high frequency in more cancers than any other tumor suppressor gene. Beyond the loss of wild-type p53 functions, mutations in the TP53 gene often lead to the expression of full-length proteins with new malignant properties. Among the defined oncogenic functions of mutant p53 is its effect on cell metabolism and autophagy. Due to the importance of autophagy as a stress adaptive response, it is frequently dysfunctional in human cancers. However, the role of p53 is enigmatic in autophagy regulation. While the complex action of the wild-type p53 on autophagy has extensively been described in literature, in this review, we focus on the conceivable role of distinct mutant p53 proteins in regulating different autophagic pathways and further discuss the available evidence suggesting a possible autophagy stimulatory role of mutant p53. Moreover, we describe the involvement of different autophagic pathways in targeting and degrading mutant p53 proteins, exploring the potential strategies of targeting mutant p53 in cancer by autophagy.

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Metabolic stress controls mutant p53 R248Q stability in acute myeloid leukemia cells

Cited by 22 publications

References 51 publications

Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells

Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells

Single Cell Detection of the p53 Protein by Mass Cytometry

Mutant p53 as a Regulator and Target of Autophagy

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