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Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells.

Sauer L, Gitenay D, Vo C, Baron VT - Oncogene (2010)

Bottom Line: Egr-1 increased the transcription of HB-EGF (epidermal growth factor), amphiregulin and epiregulin, resulting in autocrine activation of the EGF receptor (EGFR) and downstream MEK/ERK cascade.Thus, mutant p53 initiates a feedback loop that involves ERK1/2-mediated transactivation of Egr-1, which in turn increases the secretion of EGFR ligands and stimulates the EGFR signaling pathway.Finally, p53 may further regulate this feedback loop by altering the level of EGFR expression.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Research Institute of San Diego, San Diego, CA 92121, USA.

ABSTRACT
Early growth response-1 (Egr-1) is overexpressed in human prostate tumors and contributes to cancer progression. On the other hand, mutation of p53 is associated with advanced prostate cancer, as well as with metastasis and hormone independence. This study shows that in prostate cell lines in culture, Egr-1 overexpression correlated with an alteration of p53 activity because of the expression of SV40 large T-antigen or because of a mutation in the TP53 gene. In cells containing altered p53 activity, Egr-1 expression was abolished by pharmacological inhibition or RNAi silencing of p53. Although forced expression of wild-type p53 was not sufficient to trigger Egr-1 transcription, four different mutants of p53 were shown to induce Egr-1. Direct binding of p53 to the EGR1 promoter could not be detected. Instead, Egr-1 transcription was driven by the ERK1/2 pathway, as it was abrogated by specific inhibitors of MEK. Egr-1 increased the transcription of HB-EGF (epidermal growth factor), amphiregulin and epiregulin, resulting in autocrine activation of the EGF receptor (EGFR) and downstream MEK/ERK cascade. Thus, mutant p53 initiates a feedback loop that involves ERK1/2-mediated transactivation of Egr-1, which in turn increases the secretion of EGFR ligands and stimulates the EGFR signaling pathway. Finally, p53 may further regulate this feedback loop by altering the level of EGFR expression.

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Proposed model of a positive feedback loop regulated by p53The dashed arrow represents the apparent initiating event.
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Figure 8: Proposed model of a positive feedback loop regulated by p53The dashed arrow represents the apparent initiating event.

Mentions: Egr-1, in turn, induces the transcription and increases the secretion of EGFR ligands, resulting in autocrine activation of the receptor. We propose a model, shown in Figure 8, which illustrates this positive feedback mechanism. Notably, this loop did not exist in cells containing wt-p53, which exhibited low levels of Egr-1.


Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells.

Sauer L, Gitenay D, Vo C, Baron VT - Oncogene (2010)

Proposed model of a positive feedback loop regulated by p53The dashed arrow represents the apparent initiating event.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2865566&req=5

Figure 8: Proposed model of a positive feedback loop regulated by p53The dashed arrow represents the apparent initiating event.
Mentions: Egr-1, in turn, induces the transcription and increases the secretion of EGFR ligands, resulting in autocrine activation of the receptor. We propose a model, shown in Figure 8, which illustrates this positive feedback mechanism. Notably, this loop did not exist in cells containing wt-p53, which exhibited low levels of Egr-1.

Bottom Line: Egr-1 increased the transcription of HB-EGF (epidermal growth factor), amphiregulin and epiregulin, resulting in autocrine activation of the EGF receptor (EGFR) and downstream MEK/ERK cascade.Thus, mutant p53 initiates a feedback loop that involves ERK1/2-mediated transactivation of Egr-1, which in turn increases the secretion of EGFR ligands and stimulates the EGFR signaling pathway.Finally, p53 may further regulate this feedback loop by altering the level of EGFR expression.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Research Institute of San Diego, San Diego, CA 92121, USA.

ABSTRACT
Early growth response-1 (Egr-1) is overexpressed in human prostate tumors and contributes to cancer progression. On the other hand, mutation of p53 is associated with advanced prostate cancer, as well as with metastasis and hormone independence. This study shows that in prostate cell lines in culture, Egr-1 overexpression correlated with an alteration of p53 activity because of the expression of SV40 large T-antigen or because of a mutation in the TP53 gene. In cells containing altered p53 activity, Egr-1 expression was abolished by pharmacological inhibition or RNAi silencing of p53. Although forced expression of wild-type p53 was not sufficient to trigger Egr-1 transcription, four different mutants of p53 were shown to induce Egr-1. Direct binding of p53 to the EGR1 promoter could not be detected. Instead, Egr-1 transcription was driven by the ERK1/2 pathway, as it was abrogated by specific inhibitors of MEK. Egr-1 increased the transcription of HB-EGF (epidermal growth factor), amphiregulin and epiregulin, resulting in autocrine activation of the EGF receptor (EGFR) and downstream MEK/ERK cascade. Thus, mutant p53 initiates a feedback loop that involves ERK1/2-mediated transactivation of Egr-1, which in turn increases the secretion of EGFR ligands and stimulates the EGFR signaling pathway. Finally, p53 may further regulate this feedback loop by altering the level of EGFR expression.

Show MeSH
Related in: MedlinePlus