Contribution of protein kinase C to ET-1-induced proliferation in human myometrial cells

Tertrin-Clary, C.; Eude, Isabelle; Fournier, Thérèse; Paris, Brigitte; Breuiller-Fouché, Michelle; Ferré, Françoise

doi:10.1152/ajpendo.1999.276.3.e503

Cited by 11 publications

(8 citation statements)

References 34 publications

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“…Although this interpretation of our data is attractive, there is no information on leiomyoma through which to address this issue. The translocation of PKCÂ following ET-1 treatment is consistent with our previous findings in which this isoform has emerged as critical for mitogenic signal transduction in human myometrial cells [6]. The functional significance of PKCÂ has not yet been identified in a tumor originating in uterine smooth muscle, but experiments on HEC1-B cells, a human endometrial adenocarcinoma cell line, have shown a selective redistribution of PKCÂ in response to a phorbol ester [20].…”

Section: Discussionsupporting

confidence: 90%

“…That endothelin-1 (ET-1) might be a new regulator of the growth of uterine tumors is supported by the presence of functional ET A receptors (ET-1 selective) in leiomyoma [2][3][4]. Only these ET A receptors are involved in the mitogenic effect of ET-1 in cultured human myometrial cells [5] and substantial evidence indicates that the protein kinase C (PKC)-signaling pathway is required for ET-1-induced myometrial cell growth [6]. The demonstration that PKC may regulate this proliferative effect makes reasonable the hypothesis that the enzyme is a pivotal regulator of uterine cell growth.…”

Section: Introductionmentioning

confidence: 99%

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Differential Regulation of Protein Kinase C Isoforms in Human Uterine Leiomyoma

Eude

Tertrin-Clary²,

Vacher-Lavenu³

et al. 2001

Gynecol Obstet Invest

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The protein kinase C (PKC) isoenzyme expression pattern in human uterine leiomyoma was compared with that obtained in homologous myometrium distal from the tumor. The six PKC isoforms (PKCα, PKCβ1, PKCβ2, PKCδ, PKCΕ and PKCζ) evidenced in the myometrium were found to be similarly expressed in leiomyoma. Quantitative immunoblotting revealed that all PKC isoforms were preferentially localized in the particulate fraction. To gain insight into the possible functional consequences of PKC expression patterns, subcellular redistribution in response to the mitogenic peptide endothelin-1 (ET-1) was studied. After stimulation with ET-1, differential redistribution occurred in leiomyoma and myometrium, suggesting a selective role of PKC isoforms in the myometrial growth process.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Differential Regulation of Protein Kinase C Isoforms in Human Uterine Leiomyoma

Eude

Tertrin-Clary²,

Vacher-Lavenu³

et al. 2001

Gynecol Obstet Invest

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“…Similarly, in bovine tracheal smooth muscle cells ET-1-induced DNA synthesis and ERK 1/2 activation are inhibited by pretreatment with PTX or following PKC downregulation [21]. ET-1-induced DNA synthesis is also inhibited in myometrial cells and immortalized Rat-1 fibroblasts following PKC downregulation [17,39,40]. On the other hand, PTX has no effect on ET-1 induced, ETA receptor-dependent DNA synthesis in renal mesangial cells [41].…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 Regulates Proliferative Responses, both alone and Synergistically with PDGF, in Rat Tracheal Smooth Muscle Cells

Yahiaoui

Villeneuve

Valderrama-Carvajal

et al. 2006

Cell Physiol Biochem

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The peptide, endothelin-1 (ET-1) regulates proliferative responses in numerous cell types. Recently, a dual ET receptor antagonist was shown to prevent the increase in airway smooth muscle cell (SMC) proliferation that accompanies airway smooth muscle remodeling in a rat model of experimental asthma. Thus, we used [3H]-thymidine incorporation assays and western immunoblotting to identify signaling pathways that regulate proliferative responses in cultured rat tracheal SMC. Our data indicate that ET-1 activation of the ET A receptor subtype induced [3H]-thymidine incorporation and activation of ERK 1/2 in primary rat tracheal SMC. ET-1-induced [3H]-thymidine incorporation and activation of ERK 1/2 were inhibited by pretreatment of SMC with pertussis toxin or down regulation of phorbol ester responsive isoforms of PKC. While ET- 1-induced ERK 1/2 activation was unaffected following inhibition of Rho kinase, ET-1-induced [3H]-thymidine incorporation was abrogated. ET-1 also potentiated [3H]-thymidine incorporation as well as cell proliferation of SMC stimulated with PDGF-BB and this response did not appear to be regulated by ERK1/ 2. These data demonstrate that ET-1 induces activation of multiple G proteins that regulate rat tracheal SMC proliferative responses, likely through signaling pathways downstream of ERK1/2 and Rho kinase.

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“…The experiments were carried out at as previously described with cultured human myometrial cells (14). Subconfluent leiomyoma cells were left untreated or treated with 0.1 mmol/l PDB for 48 h in serum-free medium and subsequently washed twice with PBS.…”

Section: Western Blot Analysis Of Pkcmentioning

confidence: 99%

“…Conventionally, calcium, protein kinase C (PKC) and protein tyrosine kinase (PTK) signaling pathways are thought to contribute to ET-1-induced cell growth and differentiation. However, in normal human myometrial cells, substantial evidence indicates that only the activation of PKC is required for ET-1-induced proliferation (14). PKCs constitute an expanding multigene family, so far with 12 known isoforms classified into three subfamilies on the basis of their structure and ability to bind cofactors.…”

Section: Introductionmentioning

confidence: 99%

Potentiation response of cultured human uterine leiomyoma cells to various growth factors by endothelin-1: role of protein kinase C

Eude

Dallot

et al. 2001

European Journal of Endocrinology

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Objective: Factors responsible for the abnormal proliferation of myometrial cells that accompanies leiomyoma formation are unknown, although steroid hormones and peptide growth factors have been implicated. We hypothesized that endothelin-1 (ET-1) is a physiological regulator of tumor growth. Design: In this study, we investigated the role of ET-1 on growth of human leiomyoma cells and its synergistic effect with growth factors, as well as the signaling pathway involved in this interaction. Methods: Leiomyoma cell proliferation was assayed by [3 H]thymidine incorporation and cell number. Protein kinase C (PKC) isoforms were analyzed by Western blot using specific antibodies. Results: ET-1 on its own was unable to stimulate DNA synthesis but potentiated the leiomyoma cell growth effects of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), IGF-I and IGF-II. The failure of a protein tyrosine kinase (PTK) inhibitor, tyrphostin 51, to affect the potentiating effect of ET-1, supports the hypothesis of non-involvement of PTK in this process. The inhibition of PKC by calphostin C or its down-regulation by phorbol 12,13-dibutyrate (PDB) eliminated the potentiating effect of ET-1, but did not block cell proliferation induced by the growth factors alone. Five PKC isoforms (a, b1, e, d and z) were detected in leiomyoma cells, but only phorbol ester-sensitive PKC isoforms (PKCa, e and d) contribute to the potentiating effect of leiomyoma cell growth by ET-1. Conclusions: We have demonstrated that ET-1 potentiates leiomyoma cell proliferation to growth factors through a PKC-dependent pathway. These findings suggest a possible involvement of ET-1 in the pathogenesis of leiomyomas.

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Contribution of protein kinase C to ET-1-induced proliferation in human myometrial cells

Cited by 11 publications

References 34 publications

Differential Regulation of Protein Kinase C Isoforms in Human Uterine Leiomyoma

Differential Regulation of Protein Kinase C Isoforms in Human Uterine Leiomyoma

Endothelin-1 Regulates Proliferative Responses, both alone and Synergistically with PDGF, in Rat Tracheal Smooth Muscle Cells

Potentiation response of cultured human uterine leiomyoma cells to various growth factors by endothelin-1: role of protein kinase C

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