Role of Ras-dependent ERK activation in phorbol ester-induced endothelial cell barrier dysfunction

Verin, Alexander D.; Liu, Feng; Bogatcheva, Natalia V.; Borbiev, Talaibek; Hershenson, Marc B.; Wang, Peiyi; Garcia, Joe G.N.

doi:10.1152/ajplung.2000.279.2.l360

Cited by 86 publications

(107 citation statements)

References 59 publications

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“…In addition, PKC, independent of Ras, plays a critical role in angiotensininduced Raf1 and MEK activation in cardiac myocytes (Zou et al, 1996), and PKCd activates the MEK/ERK pathway, independent of Ras but dependent on Raf activation, in COS and NIH-3T3 cells (Ueda et al, 1996;Seternes et al, 1999). In contrast, other studies have shown that PMA/PKC regulates downstream gene induction and functions through sequential induction of Ras, Raf and MEK (Chiloeches et al, 1999;Verin et al, 2000;Vuong et al, 2000); these effects appear to be dependent on cellular context. In our present study, cotransfection with a dominant-negative Raf effectively inhibited TRAF1 promoter induction by PMA.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-κB-dependent pathway

Wang

et al. 2004

Oncogene

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Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are cytoplasmic adapter proteins that link a wide variety of cell surface receptors to the apoptotic signaling cascade. The purpose of this study was to delineate the signaling pathways and TRAF1 promoter elements responsible for phorbol ester-mediated TRAF1 induction in human colon cancers. Here, we found that the PKC activators, phorbol 12-myristate 13-acetate (PMA) and bryostatin I, induced TRAF1 mRNA expression; pretreatment with actinomycin D blocked PMA-mediated TRAF1 expression suggesting induction at the transcriptional level. In contrast, expression of other TRAFs (TRAF2, 3 and 4) was minimally altered by PMA. Various PKC isoform-selective inhibitors blocked PMAmediated TRAF1 mRNA and promoter stimulation; rottlerin, a selective PKCd inhibitor, had no effect suggesting that Ca 2 þ -dependent PKC isoforms (e.g., PKCa and bI) play a role in TRAF1 regulation. In addition, the MEK/ERK inhibitors, PD98059 and UO126, suppressed PMA-stimulated TRAF1 promoter activity indicating a role for ERK in TRAF1 induction. Moreover, cotransfection of a dominant-negative Raf-1 (Raf-C4) significantly reduced PMA-stimulated TRAF1 promoter activity whereas transfection of dominantnegative Ras or treatment with Ras inhibitors had minimal to no effect on TRAF1 induction suggesting dependence on Raf, but not Ras, activation. Finally, site-specific mutagenesis of functional NF-jB sites (particularly the most proximal site) in the TRAF1 promoter significantly decreased PMA-mediated promoter activity. In conclusion, our results demonstrate selective induction of TRAF1 in human colon cancer cells through a Ca 2 þ -dependent PKC/Raf-1/ERK/NF-jB-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

“…Raf-1, but not Ras, mediates TRAF1 activation by PMA PMA/PKC can activate MEK/ERK through Rasdependent or -independent pathways (Ueda et al, 1996;Verin et al, 2000;Vuong et al, 2000;Zhao et al, 2001). We next determined the role of Ras and Raf in TRAF1 stimulation.…”

Section: Involvement Of Mek/erk In Traf1 Stimulation By Pmamentioning

confidence: 99%

Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-κB-dependent pathway

Wang

et al. 2004

Oncogene

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“…Another well-known effect of PMA is the activation of Erk1/2 MAP kinase pathway (Frost et al, 1994;Verin et al, 2000). At least three of the five protein classes directly activated by PMA (i.e., PKC, Ras-GRP, chimaerin) could transduce their transcriptional signals via the MAP kinase pathway (Kazanietz, 2002).…”

Section: Pv1 Upregulation Requires the Activation Of Erk1/2 Map Kinasmentioning

confidence: 99%

PV1 Is a Key Structural Component for the Formation of the Stomatal and Fenestral Diaphragms

Stan

Tkachenko²,

Niesman

2004

MBoC

125

156

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PV1 is an endothelial-specific integral membrane glycoprotein associated with the stomatal diaphragms of caveolae, transendothelial channels, and vesiculo-vacuolar organelles and the diaphragms of endothelial fenestrae. Multiple PV1 homodimers are found within each stomatal and fenestral diaphragm. We investigated the function of PV1 within these diaphragms and their regulation and found that treatment of endothelial cells in culture with phorbol myristate acetate (PMA) led to upregulation of PV1. This correlated with de novo formation of stomatal diaphragms of caveolae and transendothelial channels as well as fenestrae upon PMA treatment. The newly formed diaphragms could be labeled with anti-PV1 antibodies. The upregulation of PV1 and formation of stomatal and fenestral diaphragms by PMA was endothelium specific and was the highest in microvascular endothelial cells compared with their large vessel counterparts. By using a siRNA approach, PV1 mRNA silencing prevented the de novo formation of the diaphragms of caveolae as well as fenestrae and transendothelial channels. Overexpression of PV1 in endothelial cells as well as in cell types that do not harbor caveolar diaphragms in situ induced de novo formation of caveolar stomatal diaphragms. Lastly, PV1 upregulation by PMA required the activation of Erk1/2 MAP kinase pathway and was protein kinase C independent. Taken together, these data show that PV1 is a key structural component, necessary for the biogenesis of the stomatal and fenestral diaphragms.

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“…MAPK inhibitor: PD98059 (2-(2-Hydroxyethylamino)-6-benzylamino-9-methylpurine; Calbiochem; Verin et al 2000, Xiao et al 2004) was injected as a single dose of 0·5, 5, 50 µg in 4 µL of 0·1% DMSO.…”

Section: Treatmentsmentioning

confidence: 99%

Inositol triphosphate participates in an oestradiol nongenomic signalling pathway involved in accelerated oviductal transport in cycling rats

Orihuela¹,

Parada-Bustamante²,

Zuñiga³

et al. 2006

Journal of Endocrinology

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Oestradiol (E 2 ) accelerates oviductal transport of oocytes in cycling rats through a nongenomic pathway that involves the cAMP-PKA signalling cascade. Here we examined the role of the inositol triphosphate (IP3) and mitogen-activated protein kinase (MAPK) signalling cascades in this nongenomic pathway. Oestrous rats were injected with E 2 s.c. and intrabursally (i.b) with the selective inhibitors of phospholipase C (PLC) ET-18-OCH 3 or MAPK PD98059. The number of eggs in the oviduct assessed 24 h later showed that ET-18-OCH 3 blocked E 2 -induced egg transport acceleration, whereas PD98059 had no effect. Other oestrous rats were treated with E 2 s.c. and 1, 3 or 6 h later oviducts were excised and the levels of IP3 and phosphorylated MAPK p44/42 (activated) were determined by radioreceptor assay and western blot, respectively. Oestradiol administration increased IP3 level at 1 and 6 h after treatment, whereas activated MAPK p44/42 level was unchanged. Finally, we explored whether cAMP-PKA and PLC-IP3 signalling cascades are coupled. Inhibition of adenylyl cyclase by i.b. injection of SQ 22536 blocked the increase of IP3 levels induced by E 2 , while inhibition of PLC by ET-18-OCH 3 had no effect on E 2 -induced PKA activity. Furthermore, activation of adenylyl cylase by Forskolin increased oviductal IP3 levels. Thus, activation of PLC-IP3 by E 2 requires previous stimulation of cAMP-PKA. We conclude that the nongenomic pathway utilised by E 2 to accelerate oviductal transport of oocytes in cycling rats involves successive activation of the cAMP-PKA and PLC-IP3 signalling cascades and does not require activation of MAPK. These findings clearly illustrate a nongenomic pathway triggered by E 2 that regulates a complex physiologic process accomplished by an entire organ.

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Role of Ras-dependent ERK activation in phorbol ester-induced endothelial cell barrier dysfunction

Cited by 86 publications

References 59 publications

Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-κB-dependent pathway

Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-κB-dependent pathway

PV1 Is a Key Structural Component for the Formation of the Stomatal and Fenestral Diaphragms

Inositol triphosphate participates in an oestradiol nongenomic signalling pathway involved in accelerated oviductal transport in cycling rats

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