p53 performs an essential role in mediating the oncogenic stimulus triggered by loss of expression of neurofibromatosis type 2 during in vitro tumor progression

Li, Xiye; Chen, Hongsai; Xue, Lu; Pang, Xiuhua; Zhang, Xiaoman; Zhu, Zhengjie; Zhu, Weidong; Wang, Zhaoyan; Wu, Hao

doi:10.3892/ol.2017.6445

Cited by 7 publications

(5 citation statements)

References 33 publications

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“…Additionally, an analysis of CDK4 induction, a molecular partner of cyclin D1 in the CCND1-CDK4/6 complex, was conducted. In cell lines with inactivated TP53, the level of CDK4 was approximately 2–2.5 times higher than in wild-type cells, as previously observed [ 43 ]. Upon addition of bleomycin, CDK4 behaved differently from Atox1 and cyclin D1 – its induction was slightly reduced, but when combined with drugs, its level remained higher than the intact control.…”

Section: Resultssupporting

confidence: 82%

Atox1-cyclin D1 loop activity is critical for survival of tumor cells with inactivated TP53

Kuchur,

Pogodaeva,

Shcherbakova

et al. 2024

Bioscience Reports

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The search for relevant molecular targets is one of the main tasks of modern tumor chemotherapy. To successfully achieve this, it is necessary to have the most complete understanding of the functioning of a transcriptional apparatus of the cell, particularly related to proliferation. The p53 protein plays an important role in regulating processes such as apoptosis, repair, and cell division, and the loss of its functionality often accompanies various types of tumors and contributes to the development of chemoresistance. Additionally, the proliferative activity of tumor cells is closely related to the metabolism of transition metals. For example, the metallochaperone Atox1 – a copper transporter protein - acts as a transcription activator for cyclin D1, promoting progression through the G1/S phase of the cell cycle. On the other hand, p53 suppresses cyclin D1 at the transcriptional level, thereby these proteins have divergent effects on cell cycle progression. However, the contribution of the interaction between these proteins to cell survival is poorly understood. This work demonstrates that not only exists a positive feedback loop between Atox1 and cyclin D1, but also that the activity of this loop depends on the status of the TP53 gene. Upon inactivation of TP53 in A549 and HepG2 cell lines, the expression of ATOX1 and CCND1 genes is enhanced, and their suppression in these cells leads to pronounced apoptosis. This fundamental observation may be useful in selecting more precise interventions for combined therapy of p53-negative tumors.

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Section: Resultssupporting

confidence: 82%

Atox1-cyclin D1 loop activity is critical for survival of tumor cells with inactivated TP53

Kuchur,

Pogodaeva,

Shcherbakova

et al. 2024

Bioscience Reports

View full text Add to dashboard Cite

show abstract

“…In Additionally, an analysis of CDK4 induction, a molecular partner of cyclin D1 in the CCND1-CDK4/6 complex, was conducted. In cell lines with inactivated TP53, the level of CDK4 was approximately 2-2.5 times higher than in wild-type cells, as previously observed [45]. Upon addition of bleomycin, CDK4 behaved differently from Atox1 and cyclin D1 -its induction was slightly reduced, but when combined with drugs, its level remained higher than the intact control.…”

Section: Bleomycin-induced P53 Activation Leads To the Suppression Ofsupporting

confidence: 76%

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

Kuchur,

Pogodaeva,

Shcherbakova

et al. 2024

Preprint

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The search for relevant molecular targets is one of the main tasks of modern tumor chemotherapy. To successfully achieve this, it is necessary to have the most complete understanding of the functioning of the cell's transcriptional apparatus, particularly related to proliferation. The p53 protein plays an important role in regulating processes such as apoptosis, repair, and cell division, and the loss of its functionality often accompanies various types of tumors and contributes to the development of chemoresistance. Additionally, the proliferative activity of tumor cells is closely related to the metabolism of transition metals. For example, the metallochaperone Atox1, a copper transporter protein, acts as a transcription activator for cyclin D1, promoting progression through the G1/S phase of the cell cycle. On the other hand, p53 suppresses cyclin D1 at the transcriptional level, thereby these proteins have divergent effects on cell cycle progression. However, the contribution of the interaction between these proteins to cell survival is poorly understood. This work demonstrates that there not only exists a positive feedback loop between Atox1 and cyclin D1, but also that the activity of this loop depends on the status of the TP53 gene. Upon inactivation of TP53 in A549 and HepG2 cell lines, the expression of ATOX1 and CCND1 genes is enhanced, and their suppression in these cells leads to pronounced apoptosis. This fundamental observation may be useful in selecting more precise interventions for combined therapy of p53-negative tumors.

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“…Furthermore, NF2(-/-) SC-like cells overexpressed inflammatory response, ROS and NFkB-related pathways, most probably by Rac1 deregulation as described in NF2-tumor models and merlin-deficient cells (53,(64)(65)(66)(67). Finally, merlin-deficient SC-like cells also showed upregulation of TP53, VEGF and epithelial-to-mesenchymal transition signaling, which is known to be deregulated in schwannomas (17,53,(68)(69)(70)(71)(72). These results confirmed the strong correlation between the described and observed changes in signaling pathways and gene expression due to merlin deficiency, suggesting that the cells developed in this study could be a reliable in vitro human NF2 SC model system to study the molecular pathogenesis of NF2.…”

Section: Discussionmentioning

confidence: 95%

MERLIN-DEFICIENT iPSCs AS ANIN VITROMODEL SYSTEM FOR STUDIYNGNF2PATHOGENESIS

Catasus

Torres‐Martín

Negro

et al. 2022

Preprint

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Background: The appearance of bilateral vestibular schwannomas (VS) is one of the most characteristic features of NF2-related schwannomatosis (NF2-related SWN), an autosomal dominant syndrome that predisposes to the development of tumours of the nervous system. VS are caused by the bi-allelic inactivation of the NF2 gene in a cell of the Schwann cell lineage. Our current understanding of VS initiation and progression as well as the development of new effective therapies is hampered by the absence of human non-perishable cell-based models. Principal Findings: We generated and characterized induced pluripotent stem cell (iPSC) lines with single or bi-allelic inactivation of NF2 by combining the direct reprogramming of VS cells with the use of CRISPR/Cas9 editing. Despite the difficulty of maintaining merlin-deficient iPSCs, we were able to differentiate them into neural crest (NC) cells. At this stage, these cells showed spontaneous expression of the SC marker S100B and the impossibility of generating Schwann cells in 2D cultures. Nevertheless, by applying a 3D Schwann cell differentiation protocol, we successfully generated NF2(+/-) and NF2(-/-) spheroids homogeneously expressing classical markers of the NC-SC axis. Conclusions: Our results show a critical function of NF2 for both reprograming and maintaining a stable pluripotent state. In addition, merlin-deficient cultures also denoted an altered differentiation capacity of merlin-deficient cells towards the NC-SC axis, in the in vitro conditions used. Finally, the generated NF2(+/-) and NF2(-/-) spheroids show potential as a genuine in vitro model of NF2-related tumours.

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p53 performs an essential role in mediating the oncogenic stimulus triggered by loss of expression of neurofibromatosis type 2 during in vitro tumor progression

Cited by 7 publications

References 33 publications

Atox1-cyclin D1 loop activity is critical for survival of tumor cells with inactivated TP53

Atox1-cyclin D1 loop activity is critical for survival of tumor cells with inactivated TP53

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

MERLIN-DEFICIENT iPSCs AS ANIN VITROMODEL SYSTEM FOR STUDIYNGNF2PATHOGENESIS

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