PKC δ-induced activation of MAPK pathway is required for bFGF-stimulated proliferation of coronary smooth muscle cells

Skaletz‐Rorowski, Adriane; Eschert, Heike; J, Leng; Stallmeyer, Birgit; Sindermann, Jürgen R.; Pulawski, Ewa; Breithardt, Günter

doi:10.1016/j.cardiores.2005.03.009

Cited by 24 publications

(21 citation statements)

References 29 publications

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“…PKC is a family of several isoforms. Previous studies suggest that the PKC isoenzymes ␦ and are important regulators of SMC growth and proliferation (Carlin et al, 1999;Salamanca and Khalil, 2005;Skaletz-Rorowski et al, 2005). The present experiments provided evidence that activation of ␣-and -PKC isoforms may play a role in the ␥-radiationinduced SMC apoptosis.…”

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confidence: 72%

α- and ϵ-Protein Kinase C Activity during Smooth Muscle Cell Apoptosis in Response to γ-Radiation

Claro¹,

Kanashiro²,

Oshiro³

et al. 2007

J Pharmacol Exp Ther

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The use of ␥-radiation in treatment of pelvic cancer is associated with injury of healthy surrounding tissues and disorders of intestinal motility; however, the cellular mechanisms involved are unclear. We tested the hypothesis that exposure of visceral smooth muscle cells (SMCs) to ␥-radiation induces apoptosis via activation of specific protein kinase C (PKC) isoforms. Cultured SMCs and slices from guinea pig ileum smooth muscle longitudinal layer (GPISMLL) were exposed to 10 to 50 Gy. Flow cytometry in ␥-radiated SMCs showed increased percentage of cells in the sub-G 0 /G 1 phase, a hallmark of apoptosis. ␥-Radiation-induced reduction in cell survival was partially but significantly alleviated with the PKC inhibitors. Sections of ␥-irradiated GPISMLL showed DNA fragmentation and apoptotic bodies analyzed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling method, whereas the plasma and nuclear membranes were preserved. Confocal microscopy in ␥-radiated SMCs labeled with annexin V-fluorescein showed an increase in apoptotic cells and phosphatidylserine externalization. Contraction of GPISMLL strips in response to KCl and acetylcholine was reduced in tissues exposed to 30 and 50 Gy. ␥-Radiation of GPISMLL caused an increase in PKC activity in the particulate fraction, a decrease in the cytosolic fraction, and increased particulate/cytosolic PKC activity ratio. Western blot analysis revealed significant amounts of ␣-and -PKC in the cytosolic fraction of control GPISMLL. ␥-Radiation caused an increase in the amount of ␣-and -PKC in the particulate fraction and a decrease in the cytosolic fraction. Data suggest that ␥-radiation induces apoptosis, growth arrest, and contractile dysfunction in visceral SMCs of GPISMLL via activation and translocation of ␣-and -PKC isoforms.

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confidence: 72%

α- and ϵ-Protein Kinase C Activity during Smooth Muscle Cell Apoptosis in Response to γ-Radiation

Claro¹,

Kanashiro²,

Oshiro³

et al. 2007

J Pharmacol Exp Ther

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“…In PMA-treated cells, PKCs target the Erk module at the level of both Raf-1 and MEK, through direct activatory phosphorylation or indirectly (15-21). Apart from PMA-mediated Erk activation, PKCs appear to be crucial for long term Erk activation by growth factors, including FGFs (20,[22][23][24][25], as well as for oncogenic .FGF signaling in chondrocytes leads to long term Ras/Erk activation, which appears to account for the growth inhibitory outcome of FGF treatment (8, 9). To date, little is known about chondrocyte properties of FGF signaling permitting prolonged Erk activity, although slow down-regulation of mutated FGFR3 appears to be involved (30,31).…”

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confidence: 99%

“…In PMA-treated cells, PKCs target the Erk module at the level of both Raf-1 and MEK, through direct activatory phosphorylation or indirectly (15)(16)(17)(18)(19)(20)(21). Apart from PMA-mediated Erk activation, PKCs appear to be crucial for long term Erk activation by growth factors, including FGFs (20,(22)(23)(24)(25), as well as for oncogenic Ras signaling (26 -29).…”

mentioning

confidence: 99%

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Krejčı́

Masri

Salazar

et al. 2007

Journal of Biological Chemistry

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Activating mutations in fibroblast growth factor receptor 3 (FGFR3) cause several human dwarfisms characterized by diminished long bone growth (1). In cartilage, FGFR3 alters chondrocyte proliferation and differentiation by up-regulation of cell cycle inhibitors and stimulation of cartilage matrix degradation (2-5). The anti-proliferative action of FGF 2 signaling in cartilage contrasts with the usual mitogenic response of cells to FGF stimulus (6), but the molecular basis of this paradox remains unclear. Recently, Erk MAP kinase was found as a candidate for FGFR3-mediated inhibition of chondrocyte proliferation and differentiation (7-10).Protein kinase C (PKC) comprises a family of serine/threonine kinases that phosphorylate the consensus motif RXX(S/T)XR (11). The PKCs are further divided into three subfamilies based on sequence similarities and modes of activation. The conventional PKCs (PKC␣, -␤I, -␤II, and -␥) are activated by phosphatidylserine, diacylglycerol, and Ca 2ϩ , the novel PKCs (PKC␦, -⑀, -, and -) require only phosphatidylserine and diacylglycerol, and the atypical PKCs (aPKC; PKC and -) respond to phosphatidylserine alone (12). The PKC phosphorylation motif is present in many proteins (13), implicating PKCs as broad specificity protein kinases. PKCs are involved in numerous signaling events including activation of the Erk MAP kinase pathway. This is evident by potent Erk activation in cells treated with phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), which activates both conventional PKCs and novel PKCs through binding of their diacylglycerol site (14). In PMA-treated cells, PKCs target the Erk module at the level of both Raf-1 and MEK, through direct activatory phosphorylation or indirectly (15-21). Apart from PMA-mediated Erk activation, PKCs appear to be crucial for long term Erk activation by growth factors, including FGFs (20,[22][23][24][25], as well as for oncogenic .FGF signaling in chondrocytes leads to long term Ras/Erk activation, which appears to account for the growth inhibitory outcome of FGF treatment (8, 9). To date, little is known about chondrocyte properties of FGF signaling permitting prolonged Erk activity, although slow down-regulation of mutated FGFR3 appears to be involved (30,31).

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“…PKCy has likewise been found to be proapoptotic in many systems (47). On the other hand, it is also clear that PKCy can be proliferative in some cell types (48)(49)(50) and is antiapoptotic in some systems [e.g., A172 glioma cells treated with TRAIL (8), C6 glioma cells infected with Sindbis virus (7), or non-small lung cancer lines A549, H1703, H157, H1355, and H1155 (51)]. …”

Section: Discussionmentioning

confidence: 99%

Differential Effect of Bryostatin 1 and Phorbol 12-Myristate 13-Acetate on HOP-92 Cell Proliferation Is Mediated by Down-regulation of Protein Kinase Cδ

Choi

Hyman²,

Blumberg³

2006

Cancer Research

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Bryostatin 1 is currently in clinical trials as a cancer chemotherapeutic agent. Although bryostatin 1, like phorbol 12-myristate 13-acetate (PMA), is a potent activator of protein kinase C (PKC), it induces only a subset of those responses induced by PMA and antagonizes others. We report that, in the HOP-92 non-small cell lung cancer line, bryostatin 1 induced a biphasic proliferative response, with maximal proliferation at 1 to 10 nmol/L. This biphasic response mirrored a biphasic suppression of the level of PKCD protein, with maximal suppression likewise at 1 to 10 nmol/L bryostatin 1. The typical phorbol ester PMA, in contrast to bryostatin 1, had no effect on the level of PKCD and modest suppression of cell proliferation, particularly evident at later treatment times. Flow cytometric analysis revealed changes in the fraction of cells in the G 0 -G 1 and S phases corresponding to the effects on proliferation. Cells overexpressing PKCD exhibited a lower rate of cell proliferation compared with control untreated cells and showed neither a proliferative response nor a loss of PKCD in response to bryostatin 1. Conversely, treatment with PKCD small interfering RNA significantly increased the cellular growth compared with controls. We conclude that the differential effect on cellular proliferation induced by bryostatin 1 compared with PMA reflects the differential suppression of PKCD.

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PKC δ-induced activation of MAPK pathway is required for bFGF-stimulated proliferation of coronary smooth muscle cells

Abstract: Our results show that PKC delta is required for the bFGF-stimulated c-Raf1-MEK-MAPK-c-myc signaling pathway involved in the proliferation of cSMC. Therefore, it may be an interesting therapeutic target for preventing proliferative vascular disorders.

Cited by 24 publications

References 29 publications

α- and ϵ-Protein Kinase C Activity during Smooth Muscle Cell Apoptosis in Response to γ-Radiation

α- and ϵ-Protein Kinase C Activity during Smooth Muscle Cell Apoptosis in Response to γ-Radiation

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

Differential Effect of Bryostatin 1 and Phorbol 12-Myristate 13-Acetate on HOP-92 Cell Proliferation Is Mediated by Down-regulation of Protein Kinase Cδ

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