Estradiol Stabilizes p53 Protein in Breast Cancer Cell Line, MCF–7

Okumura, Naoki; Eguchi, Hidetaka; Hayashi, Shin Ichi; Saji, Shigetoyo

doi:10.1111/j.1349-7006.2002.tb01331.x

Cited by 23 publications

(16 citation statements)

References 32 publications

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“…2C). High levels of mutant p53 protein in MDA-231 cells is consistent with other reports and could be due to the compensatory overexpression of the nonfunctional protein or failure to transactivate its negative regulator Hdm2 (18). As expected, the increase in p53 protein in response to FIP200 led to the significant increase in the levels of p53 transcriptional target, p21, in both MCF-7 and U2OS cells, but not p53 null Saos-2 cells.…”

Section: Resultssupporting

confidence: 78%

“…We also found that expression of FIP200 caused increased phosphorylation of p53 at Ser 15 and stabilization by preventing its proteasomal degradation. NH 2 -terminal p53 phosphorylation at Ser 15 , Thr 18 , and Ser 20 has been shown critical for p53 stabilization (41)(42)(43). Although all three residues have been implicated in p53 stabilization, the relative importance of each residue in regulating p53/Hdm2 interaction seems to differ among different studies (28).…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of Cell Cycle Regulation by FIP200 in Human Breast Cancer Cells

Melkoumian

Gan

et al. 2005

Cancer Research

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FIP200 is a novel protein inhibitor for focal adhesion kinase (FAK), which binds to FAK directly and inhibits its kinase activity and associated cellular functions, such as cell adhesion, spreading, and motility in fibroblasts. Here we show that FIP200 inhibits G 1 -S phase progression, proliferation, and clonogenic survival in human breast cancer cells. Consistent with the G 1 arrest induced by FIP200, we found that FIP200 increased p21 and decreased cyclin D1 protein levels in breast cancer cells. In addition, FIP200 significantly induced p21 promoter activity in MCF-7 cells and this response was abolished upon deletion of p53 binding sites within p21 promoter. Furthermore, we found that FIP200 could interact with exogenous and endogenous p53 protein and significantly increase its half-life compared with the control cells. We also found that the NH 2 -terminal 154 residues of FIP200 were sufficient to mediate p53 interaction and G 1 arrest in cells. The increase in p53 half-life correlated with the increased phosphorylation at Ser 15 and decreased proteasomal degradation via ubiquitin and Hdm2-independent mechanism. Stabilization of p53 by FIP200 could be partially reversed by NQO1 inhibitor, dicoumarol. In contrast to p53, FIP200 decreased cyclin D1 protein half-life by promoting proteasome-dependent degradation of cyclin D1. In summary, our results suggest that FIP200 increases p21 protein levels via stabilization of its upstream regulator p53 and decreases cyclin D1 protein by promoting its degradation. Both effects are critical for FIP200-induced G 1 arrest and may contribute to the putative antitumor activities of FIP200 in breast cancer. (Cancer Res 2005; 65(15): 6676-84)

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Mechanism of Cell Cycle Regulation by FIP200 in Human Breast Cancer Cells

Melkoumian

Gan

et al. 2005

Cancer Research

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“…Treating MCF-7 cells with p53 siRNA also decreased KLF4 protein and mRNA levels, suggesting that p53 regulates the transcription of KLF4 (Figure 5b, c). Earlier reports have shown that estrogen induces accumulation of wild-type p53 protein through ERa (Okumura et al, 2002). Moreover, we and other groups have shown that p53 enhances KLF4 expression (Figures 5b and c; Zhang et al, 2000;Yoon et al, 2003;Yoon and Yang, 2004).…”

Section: Resultssupporting

confidence: 66%

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

et al. 2009

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Kruppel-like factor 4 (KLF4) is a transcription factor that participates in both tumor suppression and oncogenesis. To determine the association of KLF4 with tumorigenesis, we integrated data assembled in the Oncomine database and discovered a decrease in KLF4 gene transcripts in breast cancers. Further analysis of the database also showed a correlation between KLF4 expression and estrogen receptor-a (ERa) positivity. Knockdown of KLF4 in MCF-7 cells elevated the growth rate of these cells in the presence of estrogen. Therefore, we examined the interaction between KLF4 and ERa, and found that KLF4 bound to the DNA-binding region of ERa. KLF4 thus inhibits the binding of ERa to estrogen response elements in promoter regions, resulting in a reduction in ERa target gene transcription. Earlier studies have reported that KLF4 is transcriptionally activated by p53 following DNA damage. We also showed that activation of p53 decreased the transcriptional activity of ERa by elevating KLF4 expression. Our studies discovered a novel molecular network between p53, KLF4 and ERa. As both p53 and ERa are involved in cell growth and apoptosis, these results may explain why KLF4 possesses both tumor suppressive and oncogenic functions in breast cancers.

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“…Estradiol-induced wild type p53 expression in MCF-7 cells has previously been reported, and it has been suggested that the induction is an ER-mediated event and is due to ER interaction with p53, which enhances its stability [15]. Therefore, we examined whether treatment of MCF-7 cells with high concentrations estradiol affects p53 expression under low growthstimulated conditions.…”

Section: Estradiol Induces Apoptosis In Mcf-7 Cellsmentioning

confidence: 93%

JNK pathway regulates estradiol-induced apoptosis in hormone-dependent human breast cancer cells

Altiok

Koyutürk

Altiok

2006

Breast Cancer Res Treat

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Estrogen is known to stimulate breast cancer development in humans. Ironically, high doses of estrogen can induce regression of hormone-dependent breast cancer in postmenopausal women. The mechanism by which estrogen induces tumour regression in breast cancer is still unknown. We found that under low growth-stimulated conditions, high concentrations of 17-beta-estradiol (estradiol) induces apoptosis and concomitantly increases phosphorylation of c-jun in estrogen receptor (ER)-positive breast cancer cell line, MCF-7, but not in ER-negative breast cancer cell line MDA-MB 231 suggesting an ER-mediated event. Interestingly, when the c-jun NH2-terminal kinase (JNK) signalling pathway was disrupted by the JNK inhibitor SP600125, the ability of estradiol to inhibit the growth of MCF-7 cells and to induce apoptosis was completely blocked. These data suggest that JNK plays a central role in mediating the anticancer effect of high concentrations of estradiol in MCF-7 cells. Our data showing the apoptotic effect of estradiol in low growth-stimulated conditions suggest potential implications for the pharmacological control of breast cancer with high dose estrogen in postmenopausal women. Furthermore, our results indicate that augmenting JNK activity could be an efficient novel approach for treating breast cancer.

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Estradiol Stabilizes p53 Protein in Breast Cancer Cell Line, MCF–7

Cited by 23 publications

References 32 publications

Mechanism of Cell Cycle Regulation by FIP200 in Human Breast Cancer Cells

Mechanism of Cell Cycle Regulation by FIP200 in Human Breast Cancer Cells

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

JNK pathway regulates estradiol-induced apoptosis in hormone-dependent human breast cancer cells

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