ERK-ERF-EGR1, a novel switch underlying acquisition of a motile phenotype

Ben-Chetrit, Nir; Tarcic, Gabi; Yarden, Yosef

doi:10.4161/cam.22263

Cited by 11 publications

(11 citation statements)

References 41 publications

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“…We have functionally demonstrated, using primary cultured GSCs, that EGR1 plays a central role in the phospho-ERK/miR-18a*/NOTCH1/ SHH regulatory network that we previously described as crucial for the regulation of self-renewal and GSC maintenance (5). In accordance with other reports in a variety of models (8,(35)(36)(37), EGR1 expression in self-renewing GSC is highly dependent on ERK activation. In this context, EGR1 is responsible for miR18a*, SHH, and GLI1 transcriptional regulation by directly interacting with their regulatory sequences.…”

Section: Discussionsupporting

confidence: 74%

A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells

Sakakini

Turchi

Bergon

et al. 2016

Journal of Biological Chemistry

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Glioblastomas are the most common primary brain tumors, highly vascularized, infiltrating, and resistant to current therapies. This cancer leads to a fatal outcome in less than 18 months. The aggressive behavior of glioblastomas, including resistance to current treatments and tumor recurrence, has been attributed to glioma stemlike/progenitor cells. The transcription factor EGR1 (early growth response 1), a member of a zinc finger transcription factor family, has been described as tumor suppressor in gliomas when ectopically overexpressed. Although EGR1 expression in human glioblastomas has been associated with patient survival, its precise location in tumor territories as well as its contribution to glioblastoma progression remain elusive. In the present study, we show that EGR1-expressing cells are more frequent in high grade gliomas where the nuclear expression of EGR1 is restricted to proliferating/progenitor cells. We show in primary cultures of glioma stemlike cells that EGR1 contributes to stemness marker expression and proliferation by orchestrating a PDGFA-dependent growth-stimulatory loop. In addition, we demonstrate that EGR1 acts as a positive regulator of several important genes, including SHH, GLI1, GLI2, and PDGFA, previously linked to the maintenance and proliferation of glioma stemlike cells.

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Section: Discussionsupporting

confidence: 74%

A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells

Sakakini

Turchi

Bergon

et al. 2016

Journal of Biological Chemistry

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“…In other human cell contexts, EGR-1 binds to the regulatory regions of the TGFβ promoter to drive transcription (23, 24), and EGR-1 is a firmly established ERK 1/2 target (25). Consistent with these prior studies, EGR-1 is upregulated in BRAF(V600E) nevus melanocytes (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma

et al. 2015

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Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here we show that CDKN2B is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAF(V600E) activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAF(V600E), we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Further, we engineer human skin grafts containing nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma.

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“…Also unlike IEGs and DEGs, LRG mRNAs are very stable [37] with a stability similar to that of un-induced mRNAs. As we discuss in the end of this mini-review, the stable expression of LRGs is thought to be responsible for phenotypic changes such as cell migration [47]. To further stabilize the post-stimulus phenotype, some LRGs are RTK ligands that will continue to activate the RTK through an autocrine mechanism, even if the original stimulus wanes.…”

Section: Primary Late Response Genes (Plrgs)mentioning

confidence: 99%

Steering tumor progression through the transcriptional response to growth factors and stroma

Feldman¹,

Yarden²

2014

FEBS Letters

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Tumor progression can be understood as a collaborative effort of mutations and growth factors, which propels cell proliferation and matrix invasion, and also enables evasion of drug-induced apoptosis. Concentrating on EGFR, we discuss downstream signaling and the initiation of transcriptional events in response to growth factors. Specifically, we portray a wave-like program, which initiates by rapid disappearance of two-dozen microRNAs, followed by an abrupt rise of immediate early genes (IEGs), relatively short transcripts encoding transcription regulators. Concurrent with the fall of IEGs, some 30–60 minutes after stimulation, a larger group, the delayed early genes, is up-regulated and its own fall overlaps the rise of the final wave of late response genes. This late wave persists and determines long-term phenotype acquisition, such as invasiveness. Key regulatory steps in the orderly response to growth factors provide a trove of potential oncogenes and tumor suppressors.

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ERK-ERF-EGR1, a novel switch underlying acquisition of a motile phenotype

Cited by 11 publications

References 41 publications

A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells

A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells

CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma

Steering tumor progression through the transcriptional response to growth factors and stroma

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