MDM2 Overexpression, Activation of Signaling Networks, and Cell Proliferation

Singh, S. K.; Deb, Sumitra

doi:10.1007/978-94-017-9211-0_12

Cited by 13 publications

(15 citation statements)

References 120 publications

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“…Upregulation of GADD45A in melanoma cells results in inhibition of apoptotic cell death (Fayolle et al, 2008), thus this gene could be associated with inhibition of apoptosis in the carbaryl treated melanocytes. Upregulation of MDM2 is consistent with cell cycle arrest, mainly in the combined treatment group, reflective of its role in the induction of S-phase cell cycle arrest and checkpoint activation in the presence of genotoxic stimuli (Deb et al, 2014). Moreover, a number of altered genes from the qRT-PCR and the microarray data corroborates with a G1-S transition in the carbaryl treated groups, e.g.…”

Section: Discussionmentioning

confidence: 87%

Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes

Ferrucio

Tiago

Fannin

et al. 2017

Toxicology in Vitro

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Carbaryl (1-naphthyl-methylcarbamate), a broad-spectrum insecticide, has recently been associated with the development of cutaneous melanoma in an epidemiological cohort study with U.S. farm workers also exposed to ultraviolet radiation, the main etiologic factor for skin carcinogenesis. We hypothesized that carbaryl exposure may increase deleterious effects of UV solar radiation on skin melanocytes. This study aimed to characterize human melanocytes after individual or combined exposure to carbaryl (100 μM) and solar radiation (375 mJ/cm2). In a microarray analysis, carbaryl, but not solar radiation, induced an oxidative stress response, evidenced by the upregulation of antioxidant genes, such as Hemeoxygenase-1 (HMOX1), and downregulation of Microphtalmia-associated Transcription Factor (MITF), the main regulator of melanocytic activity; results were confirmed by qRT-PCR. Carbaryl and solar radiation induced a gene response suggestive of DNA damage and cell cycle alteration. The expression of CDKN1A, BRCA1/2 and MDM2 genes was notably more intense in the combined treatment group, in a synergistic manner. Flow cytometry assays demonstrated S-phase cell cycle arrest, reduced apoptosis levels and faster induction of cyclobutane pyrimidine dimers (CPD) lesions in carbaryl treated groups. Our data suggests that carbaryl is genotoxic to human melanocytes, especially when associated with solar radiation.

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Section: Discussionmentioning

confidence: 87%

Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes

Ferrucio

Tiago

Fannin

et al. 2017

Toxicology in Vitro

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“…Both Mdm2 and IRP2 are found to promote cell proliferation . Thus, to determine the biological significance of IRP2‐mediated Mdm2 expression, colony formation assay was performed with isogenic control and IRP2‐KO p53 −/− HCT116 cells transiently transfected with a control vector or a vector expressing IRP2 or Mdm2, followed with or without DFO treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Both Mdm2 and IRP2 are found to promote cell proliferation. 32,33 Thus, to determine the biological significance of IRP2-mediated Mdm2 expression, colony formation assay was performed with isogenic control and IRP2-KO p53 −/− HCT116 cells transiently transfected with a control vector or a vector expressing IRP2 or Mdm2, followed with or without DFO treatment. We found that under mock-treatment condition, loss of IRP2 led to reduced number of colonies, which can be rescued by ectopic IRP2 or Mdm2 ( Figure 6A,B and Supplemental Figure 1).…”

Section: The Irp2-mdm2 Axis Plays a Role In Cell Proliferationmentioning

confidence: 99%

Mdm2 is a target and mediator of IRP2 in cell growth control

et al. 2019

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Iron is an essential element to all living organisms and plays a vital role in many cellular processes, such as DNA synthesis and energy production. The Mdm2 oncogene is an E3 ligase and known to promote tumor growth. However, the role of Mdm2 in iron homeostasis is not certain. Here, we showed that Mdm2 expression was increased by iron depletion but decreased by iron repletion. We also showed that Iron Regulatory Protein 2 (IRP2) mediated iron‐regulated Mdm2 expression. Specifically, Mdm2 expression was increased by ectopic IRP2 but decreased by knockdown or knockout of IRP2 in human cancer cells as well as in mouse embryonic fibroblasts. In addition, we showed that IRP2‐regulated Mdm2 expression was independent of tumor suppressor p53. Mechanistically, we found that IRP2 stabilized Mdm2 transcript via binding to an iron response element (IRE) in the 3ʹUTR of Mdm2 mRNA. Finally, we showed that Mdm2 is required for IRP2‐mediated cell proliferation and Mdm2 expression is highly associated with IRP2 in both the normal and cancerous liver tissues. Together, we uncover a novel regulation of Mdm2 by IRP2 via mRNA stability and that the IRP2‐Mdm2 axis may play a critical role in cell growth.

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“…A number of intracellular and extracellular stressors, including irradiation, chemicals, oxygen-free radicals, hypoxia and very low nucleotide levels, lead to rapid activation of the p53 protein (9,10). Under these conditions, the p53 protein may be rescued from degradation, accumulate to high levels and become phosphorylated on its N-terminal activation sites (11). Among these phosphorylated sites, phosphorylation of Serine (Ser)15 and 20 have been revealed to be essential for the stabilization, induction and transactivation functioning of p53.…”

Section: Introductionmentioning

confidence: 99%

Aloin promotes A549 cell apoptosis via the reactive oxygen species-mitogen activated protein kinase signaling pathway and p53 phosphorylation

Wan

Zhang

Fan

et al. 2017

Molecular Medicine Reports

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Aloin has the potential to be a novel anticancer agent in cancer therapies. However, the detailed anticancer effect of Aloin remains to be fully elucidated. The present study analyzed the p53‑dependent mechanisms in response to Aloin treatment. Using the p53‑proficient A549 cells, an Aloin‑induced apoptotic cell model was established, which was used to evaluate the potential underlying molecular mechanisms. The results demonstrated that 200, 300 and 400 µM Aloin induced intrinsic cell apoptosis, which was further confirmed by disruption of the mitochondrial membrane potential, elevation of cytosolic Ca2+ levels, and activation of B‑cell lymphoma 2 (Bcl‑2) homologous antagonist killer, Bcl‑2 X‑associated protein, p53 upregulated modulator of apoptosis and phorbol‑12‑myristate‑13‑acetate‑induced protein 1. Aloin‑induced apoptosis was also accompanied by the induction of p53 phosphorylation on Serine (Ser)15, Threonine 18, Ser20 and Ser392; however, there were no significant differences in the expression of p53 and mouse double minute 2 homolog. Aloin‑induced apoptosis was reactive oxygen species (ROS)‑ and c‑Jun/p38‑dependent, as specific inhibitors for ROS, phosphorylated (p)‑c‑Jun and p‑p38 may attenuate Aloin‑induced A549 cell proliferating inhibition. In conclusion, these results suggested that Aloin may induce apoptosis in A549 cells via the ROS‑mitogen activated protein kinase signaling pathway, with p53 phosphorylation. These results implicate Aloin as a potential therapeutic agent for the treatment of lung cancer.

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MDM2 Overexpression, Activation of Signaling Networks, and Cell Proliferation

Cited by 13 publications

References 120 publications

Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes

Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes

Mdm2 is a target and mediator of IRP2 in cell growth control

Aloin promotes A549 cell apoptosis via the reactive oxygen species-mitogen activated protein kinase signaling pathway and p53 phosphorylation

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