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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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Related in: MedlinePlus

Mutant p53 induces Egr-1 expression(Panel A) 22Rv1 cells were treated with the indicated concentrations of Nutlin for 15 hrs before lysis. Protein expression was analyzed by western blot. (Panel B) 22Rv1 cells were mock-transfected or transfected with wild-type p53 (wt) or the indicated mutants of p53. After 72 hours, total RNA was purified and semi-quantitative RT-PCR was performed as described in Methods.
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Figure 2: Mutant p53 induces Egr-1 expression(Panel A) 22Rv1 cells were treated with the indicated concentrations of Nutlin for 15 hrs before lysis. Protein expression was analyzed by western blot. (Panel B) 22Rv1 cells were mock-transfected or transfected with wild-type p53 (wt) or the indicated mutants of p53. After 72 hours, total RNA was purified and semi-quantitative RT-PCR was performed as described in Methods.

Mentions: As shown in Figure 2A, nutlin increased the level of p53 in 22Rv1(wt-p53), but did not induce Egr-1 expression. A concomitant increase in the expression of p21CIP, a well known target of p53, serves as a positive control and indicates that even at low doses nutlin actually increased p53 activity. These results support the notion that increasing the activity of wt-p53 is not sufficient to promote the transcription 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)

Mutant p53 induces Egr-1 expression(Panel A) 22Rv1 cells were treated with the indicated concentrations of Nutlin for 15 hrs before lysis. Protein expression was analyzed by western blot. (Panel B) 22Rv1 cells were mock-transfected or transfected with wild-type p53 (wt) or the indicated mutants of p53. After 72 hours, total RNA was purified and semi-quantitative RT-PCR was performed as described in Methods.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Mutant p53 induces Egr-1 expression(Panel A) 22Rv1 cells were treated with the indicated concentrations of Nutlin for 15 hrs before lysis. Protein expression was analyzed by western blot. (Panel B) 22Rv1 cells were mock-transfected or transfected with wild-type p53 (wt) or the indicated mutants of p53. After 72 hours, total RNA was purified and semi-quantitative RT-PCR was performed as described in Methods.
Mentions: As shown in Figure 2A, nutlin increased the level of p53 in 22Rv1(wt-p53), but did not induce Egr-1 expression. A concomitant increase in the expression of p21CIP, a well known target of p53, serves as a positive control and indicates that even at low doses nutlin actually increased p53 activity. These results support the notion that increasing the activity of wt-p53 is not sufficient to promote the transcription 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