Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

He, Huan; Song, Dandan; Sinha, Indranil; Heßling, Bernd; Li, Xidan; Haldosén, Lars-Arne; Zhao, Chunyan

doi:10.1038/s41388-019-0824-4

Cited by 21 publications

(22 citation statements)

References 330 publications

(414 reference statements)

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“…Several reports on the DDX5/Dbp2 subfamily support our conclusion. DDX5 is a coactivator of transcription factor Fra-1 and DDX5 expression increases Fra-1 transcriptional activity and stimulates cell proliferation in triple-negative breast cancer cells . DDX5 interacts with transcription factor 12 and enhances proliferation of osteosarcoma cells .…”

Section: Discussionmentioning

confidence: 99%

Leucine Promotes Milk Synthesis in Bovine Mammary Epithelial Cells via the PI3K-DDX59 Signaling

Qiu

Zhen

et al. 2019

J. Agric. Food Chem.

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Leucine is an essential amino acid in the milk production of bovine mammary glands, but the regulatory roles and molecular mechanisms of leucine are still not known well. This study investigated the roles of leucine on milk synthesis and explored the corresponding mechanism in bovine mammary epithelial cells (BMECs). Leucine (0, 0.25, 0.5, 0.75, 1.0, and 1.25 mM) was added to BMECs that were cultured in FBS-free OPTI-MEM medium. Leucine significantly promoted milk protein and milk fat synthesis and also increased phosphorylation of mTOR signaling protein and the protein expression levels of SREBP-1c, with the most significant effects at 0.75 mM concentration. Leucine increased the expression and nuclear localization of DDX59, and loss and gain of gene function experiments further reveal that DDX59 mediates the stimulation of leucine on the mRNA expression variation of mTOR and SREBP-1c genes. PI3K inhibition experiment further detected that leucine upregulated expression of DDX59 and its downstream signaling via PI3K activation. ChIP-qPCR analysis further proved the binding of DDX59 to the promoter regions of mTOR and SREBP-1c. In summary, these data prove that DDX59 positively regulates the mTOR and SREBP-1c signaling pathways leading to synthesis of milk, and leucine regulates these two signaling pathways through the PI3K-DDX59 signaling.

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Section: Discussionmentioning

confidence: 99%

Leucine Promotes Milk Synthesis in Bovine Mammary Epithelial Cells via the PI3K-DDX59 Signaling

Qiu

Zhen

et al. 2019

J. Agric. Food Chem.

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“…Based on the synthetic lethality between the loss of PARP activity and BER (Base Excision Repair) defects, PARP inhibitors, such as olaparib, allow the successful treatment of BRCA1/2 mutated cancers, although ineffective in BRCA-wild-type tumors, representing most (80-85%) of TNBCs. Remarkably, PARP1 has been identified among 118 chromatin-bound Fra-1 partners, by proteomic screening in TNBC cells [86]. The interaction between PARP1 and Fra-1 results in reciprocal inhibition.…”

Section: Fra-1 In Drug Resistance and Dna Repair Mechanismsmentioning

confidence: 99%

“…More recently, screening for proteins interacting with the chromatin-bound Fra-1, the RNA helicase p68/DDX5 has been characterized as an oncogenic coactivator of Fra-1 in TNBC [86]. DDX5 is directly bound and destabilized by resveratrol, a well-known chemopreventive nutraceutical.…”

Section: Targeting the Fra-1/ap-1-mediated Transactivationmentioning

confidence: 99%

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

Casalino

Talotta²,

Cimmino

et al. 2022

Cancers

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The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells.

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“…The microRNA miR-455-3p has been shown to repress cell proliferation in colorectal cancer cells by targeting TPT1 (57), therefore representing a new potential therapeutic target for pterygia. DDX5, also among the top expressed DEG, is known to play a role in tumor cell proliferation and epithelial-mesenchymal transition in different malignancies (58)(59)(60)(61) and may therefore also represent a therapeutic approach for the treatment of pterygia. Furthermore, this study identifies FN1 as one of the key pterygia-associated factors on the RNA level, which was validated by immunohistochemistry revealing significant stromal immunoreactivity against FN1 in pterygia which was absent in controls, a finding which is in accordance with previously published results (8,10,15,16).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Cellular Microenvironment and Novel Specific Biomarkers in Pterygia Using RNA Sequencing

et al. 2022

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With a worldwide prevalence of ~12%, pterygium is a common degenerative and environmentally triggered ocular surface disorder characterized by wing-shaped growth of conjunctival tissue onto the cornea that can lead to blindness if left untreated. This study characterizes the transcriptional profile and the cellular microenvironment of conjunctival pterygia and identifies novel pterygia-specific biomarkers. Formalin-fixed and paraffin-embedded pterygia as well as healthy conjunctival specimens were analyzed using MACE RNA sequencing (n = 8 each) and immunohistochemistry (pterygia n = 7, control n = 3). According to the bioinformatic cell type enrichment analysis using xCell, the cellular microenvironment of pterygia was characterized by an enrichment of myofibroblasts, T-lymphocytes and various antigen-presenting cells, including dendritic cells and macrophages. Differentially expressed genes that were increased in pterygia compared to control tissue were mainly involved in autophagy (including DCN, TMBIM6), cellular response to stress (including TPT1, DDX5) as well as fibroblast proliferation and epithelial to mesenchymal transition (including CTNNB1, TGFBR1, and FN1). Immunohistochemical analysis confirmed a significantly increased FN1 stromal immunoreactivity in pterygia when compared to control tissue. In addition, a variety of factors involved in apoptosis were significantly downregulated in pterygia, including LCN2, CTSD, and NISCH. Furthermore, 450 pterygia-specific biomarkers were identified by including transcriptional data of different ocular surface pathologies serving as controls (training group), which were then validated using transcriptional data of cultured human pterygium cells. Among the most pterygia-specific factors were transcripts such as AHNAK, RTN4, TPT1, FSTL1, and SPARC. Immunohistochemical validation of SPARC revealed a significantly increased stromal immunoreactivity in pterygia when compared to controls, most notably in vessels and intravascular vessel wall-adherent mononuclear cells. Taken together, the present study provides new insights into the cellular microenvironment and the transcriptional profile of pterygia, identifies new and specific biomarkers and in addition to fibrosis-related genes, uncovers autophagy, stress response and apoptosis modulation as pterygium-associated processes. These findings expand our understanding of the pathophysiology of pterygia, provide new diagnostic tools, and may enable new targeted therapeutic options for this common and sight-threatening ocular surface disease.

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Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Abstract: A multi-omics approach to uncover estrogen receptor (ER) and activator protein 1 (AP-1) signaling networks in breast cancer THESIS FOR DOCTORAL DEGREE (Ph.D.

Cited by 21 publications

References 330 publications

Leucine Promotes Milk Synthesis in Bovine Mammary Epithelial Cells via the PI3K-DDX59 Signaling

Leucine Promotes Milk Synthesis in Bovine Mammary Epithelial Cells via the PI3K-DDX59 Signaling

The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting

Characterization of the Cellular Microenvironment and Novel Specific Biomarkers in Pterygia Using RNA Sequencing

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