Epidermal growth factor and thrombin induced proliferation of immortalized human keratinocytes is coupled to the synthesis of Egr‐1, a zinc finger transcriptional regulator

Kaufmann, Katrin; Thiel, Gerald

doi:10.1002/jcb.10145

Cited by 130 publications

(109 citation statements)

References 49 publications

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“…These results suggest that egr-4 is expressed in two distinct phases during regeneration, an early, Smed-egfr-3-independent, phase, and a subsequent phase that is controlled by EGFR signaling. These findings are supported by previous studies demonstrating that the expression of egr genes is regulated by the EGFR pathway in different organisms and contexts (Kaufmann and Thiel, 2002;Tsai et al, 2000, Lindzen et al, 2012.…”

Section: Egr-4 Rnai Disrupts Head Regeneration Without Impairing the supporting

confidence: 89%

egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians

et al. 2014

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During the regeneration of freshwater planarians, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/ β-catenin and Hh signaling pathways in re-establishing anteriorposterior (AP) polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its AP identity are less well understood. Previous studies have described a role of Smed-egfr-3, a planarian epidermal growth factor receptor, in blastema growth and differentiation. Here, we identify Smed-egr-4, a zinc-finger transcription factor belonging to the early growth response gene family, as a putative downstream target of Smed-egfr-3. Smed-egr-4 is mainly expressed in the central nervous system and its silencing inhibits anterior regeneration without affecting the regeneration of posterior regions. Single and combinatorial RNA interference to target different elements of the Wnt/β-catenin pathway, together with expression analysis of brain-and anterior-specific markers, revealed that Smed-egr-4: (1) is expressed in two phasesan early Smed-egfr-3-independent phase and a late Smed-egfr-3-dependent phase; (2) is necessary for the differentiation of the brain primordia in the early stages of regeneration; and (3) that it appears to antagonize the activity of the Wnt/β-catenin pathway to allow head regeneration. These results suggest that a conserved EGFR/egr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the proper progression of head regeneration.

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Section: Egr-4 Rnai Disrupts Head Regeneration Without Impairing the supporting

confidence: 89%

egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians

et al. 2014

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“…Up-regulation of EGR1 expression may result in apparently contradictory activities including mitogenesis (33,34), differentiation (35,36), tumor suppression (37), apoptosis, and protection from apoptosis (38,39). It was suggested that EGR1 exerts its activity by regulating the expression of different genes involved in various pathways.…”

Section: Discussionmentioning

confidence: 99%

Transactivation of the EGR1 Gene Contributes to Mutant p53 Gain of Function

et al. 2004

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Tumor-associated mutants of the p53 tumor suppressor protein exert biological activities compatible with an oncogenic gain of function. To explore the underlying molecular mechanism, we performed microarray analysis, comparing p53-null cells to mutant p53-expressing cells. One of the genes up-regulated in the presence of mutant p53 was EGR1, a transcription factor implicated in growth control, apoptosis, and cancer. EGR1 induction by various types of stress is markedly augmented in cells expressing mutant p53. Moreover, chromatin immunoprecipitation analysis indicates that mutant p53 is physically associated with the EGR1 promoter. Functional assays indicate that induction of EGR1 by mutant p53 contributes to enhanced transformed properties and resistance to apoptosis. We propose that EGR1 is a significant contributor to mutant p53 gain of function.

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“…Studies on glioma cells (Kaufmann and Thiel, 2001) following EGF stimulation indicated that hEGR1 may be an important part of the EGF-initiated signalling cascades and showed that hEGR1 gene transcripts and protein were undetectable in the absence of cell stimulation by EGF. A similar proposal that hEGR1 may be an important late part of the EGF signalling cascade is reported in a study of EGF and thrombin on keratinocytes (Kaufmann and Thiel, 2002). EGF induced a transient synthesis of hEGR1 with a peak between 1 and 5 h. Proliferation, activation of ERK and biosynthesis of hEGR1 was inhibited by AG1487, an EGFR specific tyrosine kinase inhibitor.…”

Section: Discussionsupporting

confidence: 78%

hEGR1 is induced by EGF, inhibited by gefitinib in bladder cell lines and related to EGF receptor levels in bladder tumours

et al. 2007

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The effect of EGF and gefitinib on two EGFR-positive human bladder cancer cell lines has been investigated using array-based gene expression profiling. The most prominent transcript, increased up to 6.7-fold by EGF compared with controls in RT112 cells, was human early growth response protein 1 (hEGR1). This induction was prevented by gefitinib. The hEGR1 mRNA in EGF-treated samples was reduced in the presence of gefitinib, as was hEGR1 protein in cell lysates. In the RT4 cells, hEGR1 expression was halved in the presence of EGF and gefitinib in combination. In bladder tumour samples, there was a significant correlation between hEGR1 mRNA detected by RT-PCR and EGFR detected by ligand binding, (P ¼ 0.042). The induction by EGF of the hEGR1 gene, mRNA and protein in RT112 cells, and its inhibition by gefitinib, together with the detection of hEGR1 mRNA in bladder tumours, suggests that hEGR1 may be important in the EGFR growth-signalling pathway in bladder cancer and should be further investigated for its prognostic significance and as a potential therapeutic target. Growth factors and their receptors are important in tumour development and progression. Several studies have shown that the presence of epidermal growth factor receptor (EGFR) in bladder cancer is associated with high tumour stage and grade and is a strong independent predictor of tumour stage progression and poor long-term survival (Neal et al, 1985(Neal et al, , 1990Lipponen and Eskelinen, 1994;Mellon et al, 1995). Bladder cancer is the fifth most common cancer in men, with an annual incidence of 24.7 per 100 000 population in the UK. 90% of bladder tumours are transitional cell carcinoma (TCC) and can be broadly divided into superficial (Ta and T1) or muscle invasive (T2, T3 and T4) forms. Approximately 50 -70% of superficial tumours recur, following removal at cystoscopy, of which 10 -20% will become invasive. At present there is no reliable method to predict which superficial tumours will show invasive progression or metastasize.EGFR is a member of the erbB family of cell surface receptors, which comprises four homologous receptors: EGFR (erbB-1/ HER1); erbB-2 (HER2/neu); erbB-3 (HER3) and erbB-4 (HER4). These receptors are composed of an extracellular ligand-binding domain, a transmembrane domain and an intracellular protein kinase domain. Ligand binding activates the EGFR by inducing homo-or hetero-dimerisation with other members of the erbB family, resulting in autophosphorylation of both intracellular tyrosine kinase domains. This initiates a cascade of intracellular signalling events that promote growth and the expression of genes involved in malignant progression (Olayioye et al, 2000). EGFR signalling is critical not only for cell proliferation but also in other processes crucial to cancer progression, and EGFR has therefore been explored as a target for anticancer therapies. One approach for the therapeutic blockade of EGFR signalling has been the discovery and development of low molecular weight compounds that inhibit the ligand-binding...

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Epidermal growth factor and thrombin induced proliferation of immortalized human keratinocytes is coupled to the synthesis of Egr‐1, a zinc finger transcriptional regulator

Cited by 130 publications

References 49 publications

egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians

egr-4, a target of EGFR signaling, is required for the formation of the brain primordia and head regeneration in planarians

Transactivation of the EGR1 Gene Contributes to Mutant p53 Gain of Function

hEGR1 is induced by EGF, inhibited by gefitinib in bladder cell lines and related to EGF receptor levels in bladder tumours

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