Rapid Activation of MAP Kinase by Estrogen in the Bone Cell Line

Endoh, Hideki; Sasaki, Hirotaka; Maruyama, Kei; Takeyama, Ken-ichi; Waga, Iwao; Shimizu, Takao; Kato, Shigeaki; Kawashima, Hiroyuki

doi:10.1006/bbrc.1997.6746

Cited by 217 publications

(134 citation statements)

References 20 publications

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“…In light of reports that estradiol induces a rapid MAPK activation (Endoh et al, 1997;Watters et al, 1997) and that a sustained rather than a transient activation of MAPK triggers di erentiation instead of proliferation (Traverse et al, 1992;, we speculate that the presence of both growth factor and hormonal signaling pathways in the same cell induces di erentiation by Figure 7 Reversion of the c-erbB-2 induced phenotype by scFv-5R transfection. Cell lysates (100 mg) were resolved on a 5 ± 15% gradient SDS polyacrylamide gel and blotted.…”

Section: Discussionmentioning

confidence: 96%

Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation

et al. 1998

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c-erbB-2, a member of the tyrosine kinase oncogene family, is overexpressed in about 30% of human breast tumors where it correlates with poor prognosis. In vitro studies have suggested that increased expression of the receptor plays an important role in malignant progression. To better understand the direct e ects of p185 HER2 overexpression, a human c-erbB-2 expression vector was transfected into the hormone-dependent MCF-7 human breast carcinoma cell line and cell growth was analysed. Unexpectedly, colony formation assay revealed a reduction in the number and size of colonies as compared with mock-transfected cells. In hormone-deprived medium, c-erbB-2 transfected cells acquired growth capability, consistent with previous reports. By contrast, two c-erbB-2-transfected clones grown in complete medium showed a reduced proliferation rate despite the activation of a fully functional oncoprotein capable of autophosphorylation and induction of the MAPK pathway. The number of c-erbB-2-overexpressing cells in the S phase of the cell cycle was about one-half the number of control and mock-transfected cells. Also, overexpression of c-erbB-2 induced overexpression of p21 WAF1 , pRB hypophosphorylation and a mature di erentiated cell phenotype with production of lipid droplets. Functional inactivation of p185 HER2 by means of a speci®c single chain antibody indicated the c-erbB-2-dependence of the observed alterations. These data show that the exogenous overexpression of the c-erbB-2 gene in hormonedependent breast cancer cells inhibits proliferation and induces di erentiation.

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Section: Discussionmentioning

confidence: 96%

Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation

et al. 1998

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“…Previous work has implicated the estrogen receptor itself as a target for growth factor signaling pathways involving Erk (3). Conversely, activation of Erk by estrogen and ER also occurs in various tissues and cell types, although the exact mechanisms remain to be determined (77,78). Even though previous studies have shown a strong association of high levels of HER-2 and PKC-␦ with hormone-independent aggressive forms of tumor cells, our results show for the first time that HER-2-and PKC-␦-mediated signaling also plays a major role in E 2 -mediated signaling in hormone-dependent, ER-positive tumor cells.…”

Section: Fig 4 Effect Of Various Pkc Inhibitors On E 2 -And Tgf␣-inmentioning

confidence: 99%

Mechanism of 17-β-Estradiol-induced Erk1/2 Activation in Breast Cancer Cells

Keshamouni¹,

Mattingly²,

Reddy³

2002

Journal of Biological Chemistry

158

135

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Activation of mitogen-activated protein kinase (Erk/ MAPK) is a critical signal transduction event for estrogen (E 2 )-mediated cell proliferation. Recent studies from our group and others have shown that persistent activation of Erk plays a major role in cell migration and tumor progression. The signaling mechanism(s) responsible for persistent Erk activation are not fully characterized, however. In this study, we have shown that E 2 induces a slow but persistent activation of Erk in MCF-7 breast carcinoma cells. The E 2 -induced Erk activation is dependent on new protein synthesis, suggesting that E 2 -induced growth factors play a major role in Erk activation. When MCF-7 cells were treated with E 2 in the presence of an anti-HER-2 monoclonal antibody (herceptin), 60 -70% of E 2 -induced Erk activation is blocked. In addition, when untreated MCF-7 cells were exposed to conditioned medium from E 2 -treated cells, Erk activity was significantly enhanced. Furthermore Erk activity was blocked by an antibody against HER-2 or by heregulin (HRG) depletion from the conditioned medium through immunoprecipitation. In contrast, epidermal growth factor receptor (Ab528) antibody only blocked 10 -20% of E 2 -induced Erk activation, suggesting that E 2 -induced Erk activation is predominantly mediated through the secretion of HRG and activation of HER-2 by an autoctine/paracrine mechanism. Inhibition of PKC-␦-mediated signaling by a dominant negative mutant or the relatively specific PKC-␦ inhibitor rottlerin blocked most of the E 2 -induced Erk activation but had no effect on TGF␣-induced Erk activation. By contrast inhibition of Ras, by inhibition of farnesyl transferase (Ftase-1) or dominant negative (N17)-Ras, significantly inhibited both E 2 -and TGF␣-induced Erk activation. This evaluation of downstream signaling revealed that E 2 -induced Erk activation is mediated by a HRG/HER-2/PKC-␦/Ras pathway that could be crucial for E 2 -dependent growth-promoting effects in early stages of tumor progression.

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“…In addition, a number of steroid hormones are reported to rapidly and reversibly activate important intermediates in signal transduction pathways known to trigger cell proliferation (Migliaccio et al, , 1998Endoh et al, 1997;Marcinkowska et al, 1997). For example estrogens activate two members in the family of c-srcrelated tyrosine kinases, c-src and c-yes as well as the MAP kinases Erk-1 and -2 (Di .…”

Section: Introductionmentioning

confidence: 99%

“…We therefore report here a rapid cellular signalling response which appears to be speci®c for the AR. a novel non-conventional mechanism (Migliaccio et al, , 1998Endoh et al, 1997;Marcinkowska et al, 1997). In this study we have asked whether androgens also mediate this response using two primary androgen responsive cells: human genital skin ®broblasts and prostatic stromal cells.…”

Section: Introductionmentioning

confidence: 99%

Rapid signalling by androgen receptor in prostate cancer cells

Peterziel¹,

Mink²,

Schonert³

et al. 1999

Oncogene

236

157

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Androgens are important growth regulators in prostate cancer. Their known mode of action in target cells requires binding to a cytoplasmic androgen receptor followed by a nuclear translocation event and modulation of the expression of speci®c genes. Here, we report another mode of action of this receptor. Treatment of androgen responsive prostate cancer cells with dihydrotestosterone leads to a rapid and reversible activation of mitogen-activated protein kinases MAPKs (also called extracellular signal-regulated kinases or Erks). Transient transfection assays demonstrated that the androgen receptor-mediated activation of MAP kinase results in enhanced activity of the transcription factor Elk-1. This action of the androgen receptor di ers from its known transcriptional activity since it is rapid and insensitive to androgen antagonists such as hydroxy¯utamide or casodex. Biochemical studies as well as analyses with dominant negative mutants showed the involvement of kinases such as MAPK/Erk kinase, phosphatidyl-inositol 3-kinase and protein kinase C in the androgen receptormediated activation of MAP kinase. These results demonstrate a novel regulatory action of the androgen receptor and prove that in addition to its known transcriptional e ects, it also uses non-conventional means to modulate several cellular signalling processes.

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Rapid Activation of MAP Kinase by Estrogen in the Bone Cell Line

Cited by 217 publications

References 20 publications

Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation

Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation

Mechanism of 17-β-Estradiol-induced Erk1/2 Activation in Breast Cancer Cells

Rapid signalling by androgen receptor in prostate cancer cells

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