The Level of Ets-1 Protein Is Regulated by Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Cancer Cells to Prevent DNA Damage

Legrand, Arnaud J.; Choul-Li, Souhaila; Spriet, Corentin; Idziorek, Thierry; Vicogne, Dorothée; Drobecq, Hervé; Dantzer, Françoise; Villeret, Vincent; Aumercier, Marc

doi:10.1371/journal.pone.0055883

Cited by 26 publications

(34 citation statements)

References 51 publications

(75 reference statements)

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“…It is therefore likely that PDGF‐BB and VEGFA function simultaneously to promote angiogenesis in CRC and that this effect is orchestrated by ETV5. The positive regulation of ETV5 by PDGF‐BB is interesting because ETS factors have been known to use positive feedforward loops as a mechanism to activate genes such as KIT and PARP1 . Thus, inhibiting either ETV5 or PDGF‐BB is expected to attenuate this signaling loop, thereby slowing angiogenesis and tumor growth.…”

Section: Discussionmentioning

confidence: 99%

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet‐derived growth factor BB

Cheng

Jin

et al. 2019

Intl Journal of Cancer

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ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease‐free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA‐seq results. Then, we identified platelet‐derived growth factor BB (PDGF‐BB) as a direct target of ETV5 that plays an important role in ETV5‐mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF‐BB could activate VEGFA expression via the PDGFR‐β/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF‐BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF‐BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.

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Section: Discussionmentioning

confidence: 99%

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet‐derived growth factor BB

Cheng

Jin

et al. 2019

Intl Journal of Cancer

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“…PARylation is a signaling mechanism involved in cellular processes, including DNA repair and apoptosis. We know from previous studies that inhibition of PARP‐1 leads to non‐ubiquitinated Ets‐1 that accumulates in the cell with an increase of its transcriptional activity. It also leads to a drastic increase in DNA damage, associated with 70% cell death.…”

Section: Discussionmentioning

confidence: 99%

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

et al. 2018

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The Ets‐1 oncoprotein is a transcription factor that promotes target gene expression in specific biological processes. Typically, Ets‐1 activity is low in healthy cells, but elevated levels of expression have been found in cancerous cells, specifically related to tumor progression. Like the vast majority of the cellular effectors, Ets‐1 does not act alone but in association with partners. Given the important role that is attributed to Ets‐1 in major human diseases, it is crucial to identify its partners and characterize their interactions. In this context, two DNA‐repair enzymes, PARP‐1 and DNA‐PK, have been identified recently as interaction partners of Ets‐1. We here identify their binding mode by means of protein docking. The results identify the interacting surface between Ets‐1 and the two DNA‐repair enzymes centered on the α‐helix H1 of the ETS domain, leaving α‐helix H3 available to bind DNA. The models highlight a hydrophobic patch on Ets‐1 at the center of the interaction interface that includes three tryptophans (Trp338, Trp356, and Trp361). We rationalize the binding mode using a series of computational analyses, including alanine scanning, molecular dynamics simulation, and residue centrality analysis. Our study constitutes a first but important step in the characterization, at the molecular level, of the interaction between an oncoprotein and DNA‐repair enzymes.

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“…A third category of biological function is for PARPs that act as transcription factors or transcription factor-binding partners, where they serve as coactivators or corepressors (87)(88)(89)(90)(91)(92)(93)(94)(95). For example, PARP1 regulates the function of several ubiquitous eukaryotic transcription factors such as specificity protein 1 (SP1), Ets-1, p53, and nuclear factor of activated T cells (NFAT) (87)(88)(89)(90)(91)(92)(93)(94)(95). PARP1 inhibits the negative elongation factor (NELF) to enhance effective transcription by RNA polymerase II (96).…”

Section: Parps As Transcription Factor Coactivators/corepressorsmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

Brady

Goel

Johnson

2019

Microbiol Mol Biol Rev

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SUMMARYThe literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

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The Level of Ets-1 Protein Is Regulated by Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Cancer Cells to Prevent DNA Damage

Cited by 26 publications

References 51 publications

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet‐derived growth factor BB

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet‐derived growth factor BB

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

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