Estrogen and raloxifene induce apoptosis by activating p38 mitogen-activated protein kinase cascade in synthetic vascular smooth muscle cells

Mori-Abe, Akiko; Tsutsumi, Seiji; Takahashi, Kazuhiro; Toya, Mayumi; Yoshida, Masahiro; Du, Botao; Koyama, Jun; Nakahara, Kenji; Takahashi, Toshifumi; Ohmichi, Masahide; Kurachi, Hirohisa

doi:10.1677/joe.0.1780417

Cited by 51 publications

(34 citation statements)

References 33 publications

(32 reference statements)

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“…However, the ability of the ERb-E2 complex to activate rapid non-genomic mechanisms has been reported (Castoria et al 2001, Kousteni et al 2001, Geraldes et al 2003, Mori-Abe et al 2003. We recently demonstrated that E2-induced rapid signal transduction pathways in ERb-transfected HeLa cells appear to play a major role in mediating antiproliferative properties of this steroid hormone.…”

Section: Introductionmentioning

confidence: 81%

“…Geraldes and coworkers reported that E2 reduces ERK/MAPK activity through ERb stimulation in porcine smooth muscle cells (Geraldes et al 2003). Moreover, contradictory evidence on the ability of ERb to activate or inactivate Src and p38 kinases have also been reported (Castoria et al 2001, Kousteni et al 2001, Geraldes et al 2003, Mori-Abe et al 2003. We recently reported the ERb-E2 Endocrine-Related Cancer (2007) 14 153-167 www.endocrinology-journals.org complex ability to activate p38/MAPK in the ER-devoid HeLa cells transiently transfected with the ERb expression vector (Acconcia et al 2005b).…”

Section: Discussionmentioning

confidence: 99%

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Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation

Galluzzo¹,

Caiazza²,

Moreno³

et al. 2007

Endocr Relat Cancer

100

115

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The cellular functions regulated by 17b-estradiol (E2) start after the hormone binds to its receptors (i.e., ERa and ERb). These act as ligand-dependent transcription factor transactivating target genes. In addition, E2 induces non-genomic actions, whose activation is triggered by a fraction of the ERs localized at the plasma membrane. Palmitoylation allows ERa to localize at the plasma membrane, to associate with caveolin-1, and, upon E2 stimulation, to activate rapid signals relevant for cell proliferation. The existence of a mechanism, which allows ERb localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ERb to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ERb or in HeLa cells transiently transfected with ERb or ERa expression vectors. As for ERa, palmitoylation is necessary for ERb localization at the plasma membrane and its association with caveolin-1 but, in contrast to ERa, the E2 binding increases ERb association with caveolin-1 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ERb-E2 complex to activate p38 impairing the receptor-dependent activation of downstream pro-apoptotic cascade (i.e., caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage). Consequently, palmitoylation must be considered to be a molecular device for ERb, which allows these receptors to interact with the plasma membrane and to regulate E2-induced non-genomic functions relevant to the antiproliferative effect of this hormone.

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Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation

Galluzzo¹,

Caiazza²,

Moreno³

et al. 2007

Endocr Relat Cancer

100

115

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“…Raloxifene also inhibited the platelet-derived growth factor-induced cell proliferation in vascular smooth muscle cells, in part through inhibition of the gene expression of cyclinD1 followed by dephosphorylation of Rb mediated by ER␣ via a transcription-dependent mechanism, a so-called genomic mechanism (11), and in part by inducing apoptosis through a p38 cascade whose activation is mediated by ER␣ via a nongenomic mechanism (12). In contrast, raloxifene, like estrogen (36 -38), induced cell proliferation in vascular endothelial cells by the up-regulation of telomerase activity via post-translational regulation of Akt-dependent phosphorylation of hTERT.…”

Section: Discussionmentioning

confidence: 99%

“…Its effect is mediated by estrogen receptor (ER) ␣ via a transcription-independent mechanism, a so-called nongenomic mechanism, and is differ-* This work was supported in part by Grants-in-aid for General Scientific entially mediated by an Akt-and ERK-dependent cascade (9 -10). In vascular smooth muscle cells, raloxifene exerts an antiproliferative effect on cells treated with platelet-derived growth factor mediated by ER␣, as estrogen does, in part via a transcription-dependent mechanism, a so-called genomic mechanism (11), and in part via a nongenomic mechanism (12).…”

mentioning

confidence: 99%

Raloxifene Increases Proliferation and Up-regulates Telomerase Activity in Human Umbilical Vein Endothelial Cells

Doshida

Ohmichi

Tsutsumi

et al. 2006

Journal of Biological Chemistry

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Vascular endothelial senescence is involved in human atherosclerosis. Telomerase activity is known to be critical in cellular senescence and its level is modulated by regulation of telomerase catalytic subunit (telomerase reverse transcriptase (TERT)) at both the transcriptional and post-transcriptional levels. Since the cardioprotective effect of estrogen itself has not been ruled out, we examined that of raloxifene, which has been classified as a selective estrogen receptor modulator, on the proliferation and telomerase activity of human umbilical vein endothelial cells (HUVECs). Raloxifene, like estrogen, clearly induced the telomerase activity and human TERT (hTERT) expression via estrogen receptor (ER) ␣ and ER␤. Treatment with raloxifene for 5 days significantly induced cell growth, and either cotreatment with a telomerase inhibitor, 3-azido-3-deoxythymidine, or transfection with hTERT-specific small interfering RNA significantly attenuated the raloxifene-induced cell growth. Raloxifene also induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase inhibitor, LY294002, significantly attenuated the raloxifene-induced telomerase activity. In addition, raloxifene induced both the phosphorylation of hTERT and IB. Moreover, cotreatment with an IB␣ phosphorylation inhibitor, BAY-11-7082, or a specific NFB nuclear translocation inhibitor, SN50, significantly attenuated the raloxifene-induced telomerase activity and the association of NFB with hTERT. These results show that raloxifene induced the up-regulation of telomerase activity not only by the transcriptional regulation of hTERT but also by posttranslational regulation of the phosphorylation of Akt and hTERT and the association of hTERT with NFB in HUVECs. Thus, the up-regulation of telomerase activity in vascular endothelial cells might be one mechanism contributing to the potential atheroprotective effect of raloxifene.The risk of cardiovascular disease steeply increases after menopause. Many epidemiological and basic studies have shown that estrogen has the significant function in the vasculature of preventing the primary development of cardiovascular disease in women (1-2). In the Women's Health Initiative, a large prospective randomized controlled study, although women on the conjugated equine estrogen-medroxyprogesterone acetate arm had an increase in the relative risk of cardiovascular events and breast cancer (3), the more recent reports indicated that on women on the conjugated equine estrogenonly treatment arm experienced a significant increase in the risk of stroke compared with women treated with placebo but did not show an increase in cardiovascular disease (4). Thus, the cardioprotective effect of estrogen itself has not been ruled out by the results of the Women's Health Initiative study.Recently, we reported that medroxyprogesterone acetate attenuates the induction of both endothelial nitric-oxide synthase (eNOS) 2 activity and NO production by estrogen in human umbilical vein endothelial cells (HUVECs) (5). Thu...

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“…2), in part through direct inhibition of gene expression of cyclin D1 followed by dephosphorylation of Rb and suppression of E2F activity mediated by ERa in a transcription-dependent manner, a so-called genomic mechanism [38] as reported the effect of estrogen on Rb phosphorylation [39,40], and in part due to induction of apoptosis through a p38 cascade whose activation is mediated by ERa in a transcriptionindependent manner, a so-called nongenomic mechanism [41] (Fig. 3).…”

Section: Vascular Smooth Muscle Cellsmentioning

confidence: 99%

Molecular Mechanism of Action of Selective Estrogen Receptor Modulator in Target Tissues

et al. 2005

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Estrogen and raloxifene induce apoptosis by activating p38 mitogen-activated protein kinase cascade in synthetic vascular smooth muscle cells

Cited by 51 publications

References 33 publications

Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation

Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation

Raloxifene Increases Proliferation and Up-regulates Telomerase Activity in Human Umbilical Vein Endothelial Cells

Molecular Mechanism of Action of Selective Estrogen Receptor Modulator in Target Tissues

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