Trophic effect in MCF-7 cells of ERα17p, a peptide corresponding to a platform regulatory motif of the estrogen receptor α—Underlying mechanisms

Gallo, Dominique; Haddad, Iman; Duvillier, Hugues; Jacquemotte, F; Laı̈os, Ioanna; Laurent, Guy; Jacquot, Yves; Vinh, Joëlle; Leclercq, Guy

doi:10.1016/j.jsbmb.2007.12.012

Cited by 26 publications

(41 citation statements)

References 67 publications

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“…Finally, potential influence of peptides deriving from proteolysis/degradation of nuclear and membrane ERs and most probably other receptors and regulatory proteins is another intriguing field not addressed here, but worthy of investigation (Gallo et al, 2008b, Kampa et al, 2001. Indeed, actions of a peptide corresponding to the hinge region of ERa have shown to modulate growth (Gallo et al, 2008a), apoptosis and migration of breast cancer cell lines. As usually in science, while an increase of knowledge fails to respond to a lot of raised questions of prominent importance it may introduce a multitude of unexpected concepts susceptible to change our life style.…”

Section: Discussionmentioning

confidence: 99%

Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis

Pelekanou¹,

Leclercq²

2011

Int. J. Dev. Biol.

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The present �or� revie�s recent � ndings related to the action of steroidal �physiolo�The present �or� revie�s recent �ndings related to the action of steroidal �physiolo� gical) estrogens on normal mammary gland development and carcinogenesis, as �ell as effects of related environmental mediators �phyto� and xeno�estrogens), the role of �hich remains controver� sial. Orchestration by estrogen receptors �i.e. ERa and ERb) and coregulators of gro�th, apoptosis and differentiation of epithelial cells, directed our analysis. The bidirectional coordination bet�een epithelium and stroma in parallel �ith maintenance of stemness are also investigated. The rele� vance of nuclear and extranuclear localization of ERs and other eventual estrogen binding sites, mediating differential actions in regard to these various topics, is critically addressed to delineate the importance of direct and indirect activation procedures and delicate feedbac� loops �ligand� induced or/and cross�tal� activation, respectively). The inclusion of the outlined regulatory concepts in drug design programs for the prevention and treatment of breast cancer may have potent effects.

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Section: Discussionmentioning

confidence: 99%

Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis

Pelekanou¹,

Leclercq²

2011

Int. J. Dev. Biol.

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“…Briefly, ERα17p contains the third nuclear localization signal of the receptor, a proteolysis site, as well as a binding site for calmodulin, a co‐regulator known to enhance both the transactivation and the stabilization of the receptor by impeding its E6‐AP (E6‐Associated Protein) mediated polyubiquitination (Li et al., 2006). We have previously reported that ERα17p elicits (pseudo)‐estrogenic responses in ERα‐expressing breast carcinoma cells by stimulating both cell proliferation and ERE‐dependent transcription in estrogen deprivation conditions, leading therefore to a proteasomal down‐regulation of ERα and a decrease of its mRNA level (Gallo et al., 2008a). Recently, another group has reported that a fragment of ERα17p (I298‐L308) prevents the phosphorylation of the serine 305 by inhibiting IGF‐1R/IRS‐1/Akt activation and by restoring aromatase inhibitor‐sensitivity in cells (Barone et al., 2010).…”

Section: Discussionmentioning

confidence: 99%

The estrogen receptor alpha‐derived peptide ERα17p (P₂₉₅‐T₃₁₁) exerts pro‐apoptotic actions in breast cancer cells in vitro and in vivo, independently from their ERα status

et al. 2010

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In recent years, our knowledge on estrogen receptors (ER) has been modified profoundly with the identification and the deciphering of the role of its protein effectors, as well as with the deeper insight of its molecular structure/function dynamics, characteristics associated with its nucleo-cytoplasmic-membrane shuttling properties. Also, significant progress has been made concerning its turn-over and associated final proteasomal degradation processes.These advances could lead in the near future to the design and the synthesis of novel receptor-interacting drugs. Recently, a number of receptor-related peptides acting as specific ER ligands have been identified and extensively studied with respect to their estrogenic/antiestrogenic activities. Among them, ERa17p, a synthetic analog of the P 295 -T 311 sequence of ERa, has been shown to exert pseudo-estrogenic effects by interacting in the close vicinity of its hinge region (BF3 domain). Remarkably, this sequence appears as the epicenter of a number of post-transcriptional modifications as well as of the recruitment of co-regulators, suggesting that it would play a key role in ERa functions. Here, we provide evidence that ERa17p induces apoptosis in ERa-positive (MCF-7, T47D) and -negative (MDA-MB-231, SK-BR-3) breast cancer cells by an ERa-independent membrane mechanism, triggering major proapoptotic signaling cascades. Finally, ERa17p induces the regression of breast ERa-negative cancer tumor xenografts, without apparent toxicity, suggesting that it could represent a new attractive tool for the development of future promising therapeutic approaches, and providing a novel insight to ER regulation of cell fate.

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“…Although we cannot totally rule out that this deletion directs an improper folding of the receptor, these data suggest that the amino acids present in the D domain are directly involved in the ER␣ repressive effect. Of interest, Gallo et al (37) have recently reported that a synthetic peptide corresponding to the P 295 -T 311 sequence mainly located in the D domain, elicits estrogenic responses in ER␣-positive breast cancer cell lines. The authors have ascribed this effect to a competitive mechanism that disrupts the repressive conformation of the aporeceptor.…”

Section: Inhibition Of Ngf Signaling By Er␣ Expressionmentioning

confidence: 99%

Different Outcomes of Unliganded and Liganded Estrogen Receptor-α on Neurite Outgrowth in PC12 Cells

et al. 2008

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A precise description of the mechanisms by which estrogen receptor-alpha (ERalpha) exerts its influences on cellular growth and differentiation is still pending. Here, we report that the differentiation of PC12 cells is profoundly affected by ERalpha. Importantly, depending upon its binding to 17beta-estradiol (17betaE2), ERalpha is found to exert different effects on pathways involved in nerve growth factor (NGF) signaling. Indeed, upon its stable expression in PC12 cells, unliganded ERalpha is able to partially inhibit the neurite outgrowth induced by NGF. This process involves a repression of MAPK and phosphatidylinositol 3-kinase/Akt signaling pathways, which leads to a negative regulation of markers of neuronal differentiation such as VGF and NFLc. This repressive action of unliganded ERalpha is mediated by its D domain and does not involve its transactivation and DNA-binding domains, thereby suggesting that direct transcriptional activity of ERalpha is not required. In contrast with this repressive action occurring in the absence of 17betaE2, the expression of ERalpha in PC12 cells allows 17betaE2 to potentiate the NGF-induced neurite outgrowth. Importantly, 17betaE2 has no impact on NGF-induced activity of MAPK and Akt signaling pathways. The mechanisms engaged by liganded ERalpha are thus unlikely to rely on an antagonism of the inhibition mediated by the unliganded ERalpha. Furthermore, 17betaE2 enhances NGF-induced response of VGF and NFLc neuronal markers in PC12 clones expressing ERalpha. This stimulatory effect of 17betaE2 requires the transactivation functions of ERalpha and its D domain, suggesting that an estrogen-responsive element-independent transcriptional mechanism is potentially relevant for the neuritogenic properties of 17betaE2 in ERalpha-expressing PC12 cells.

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Trophic effect in MCF-7 cells of ERα17p, a peptide corresponding to a platform regulatory motif of the estrogen receptor α—Underlying mechanisms

Cited by 26 publications

References 67 publications

Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis

Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis

The estrogen receptor alpha‐derived peptide ERα17p (P₂₉₅‐T₃₁₁) exerts pro‐apoptotic actions in breast cancer cells in vitro and in vivo, independently from their ERα status

Different Outcomes of Unliganded and Liganded Estrogen Receptor-α on Neurite Outgrowth in PC12 Cells

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Trophic effect in MCF-7 cells of ERα17p, a peptide corresponding to a platform regulatory motif of the estrogen receptor α—Underlying mechanisms

Cited by 26 publications

References 67 publications

Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis

Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis

The estrogen receptor alpha‐derived peptide ERα17p (P295‐T311) exerts pro‐apoptotic actions in breast cancer cells in vitro and in vivo, independently from their ERα status

Different Outcomes of Unliganded and Liganded Estrogen Receptor-α on Neurite Outgrowth in PC12 Cells

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The estrogen receptor alpha‐derived peptide ERα17p (P₂₉₅‐T₃₁₁) exerts pro‐apoptotic actions in breast cancer cells in vitro and in vivo, independently from their ERα status