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Parallel signaling pathways in endothelin-1-induced proliferation of U373MG astrocytoma cells.
Exp Biol Med (Maywood). 2007 Mar; 232(3):370-84.EB

Abstract

Endothelin-1 (ET-1) is a potent mitogen for many cells, especially when its levels are elevated under pathological conditions, as seen in tumor cell progression and astroglial activation in neuropathies. While ET-1 is known to cause astroglial proliferation, in the present study, multiple signaling pathways involved in ET-1-mediated astrocyte proliferation were characterized. Treatment with PD98059 and U0126 (MEK inhibitors) inhibited not only ET-1-induced cell proliferation but also ET-1-activated phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in U373MG astrocytoma cells. Whereas the nonselective protein kinase C (PKC) inhibitor chelerythrine attenuated ET-1-induced cell proliferation, it was unable to block ET-1-induced ERK phosphorylation. However, ET-1 did not activate conventional or novel PKCs and did not elevate intracellular calcium. In addition, U73122 (a selective phospholipase C inhibitor), FTI-277 (an H-Ras inhibitor), as well as protein tyrosine kinase inhibitors also did not abolish ET-1-induced ERK1/2 phosphorylation. ET-1 treatment increased the activity of total Ras but not H-Ras. The phosphoinositide 3-kinase (PI3K) pathway appeared to be involved in signal transduction induced by ET-1, but it did not appear to participate in cross talk with the mitogen-activated protein kinase (MAPK) pathway. Activated ET receptors did not propagate signals either through protein tyrosine kinases or transactivation of EGF receptor tyrosine kinases, which typically trigger Ras-Raf-MAPK pathways. The results indicate that ET-1 stimulates cell proliferation by the activation of MAPK-, PKC-, and PI3K-dependent pathways that appear to function in a parallel manner. There is no apparent, direct "cross talk" between these pathways in U373MG cells, but rather, they might act on the independent but necessary components of the mitogenic effects of ET-1.

Authors+Show Affiliations

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17327470

Citation

He, Shaoqing, et al. "Parallel Signaling Pathways in Endothelin-1-induced Proliferation of U373MG Astrocytoma Cells." Experimental Biology and Medicine (Maywood, N.J.), vol. 232, no. 3, 2007, pp. 370-84.
He S, Dibas A, Yorio T, et al. Parallel signaling pathways in endothelin-1-induced proliferation of U373MG astrocytoma cells. Exp Biol Med (Maywood). 2007;232(3):370-84.
He, S., Dibas, A., Yorio, T., & Prasanna, G. (2007). Parallel signaling pathways in endothelin-1-induced proliferation of U373MG astrocytoma cells. Experimental Biology and Medicine (Maywood, N.J.), 232(3), 370-84.
He S, et al. Parallel Signaling Pathways in Endothelin-1-induced Proliferation of U373MG Astrocytoma Cells. Exp Biol Med (Maywood). 2007;232(3):370-84. PubMed PMID: 17327470.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Parallel signaling pathways in endothelin-1-induced proliferation of U373MG astrocytoma cells. AU - He,Shaoqing, AU - Dibas,Adnan, AU - Yorio,Thomas, AU - Prasanna,Ganesh, PY - 2007/3/1/pubmed PY - 2007/4/17/medline PY - 2007/3/1/entrez SP - 370 EP - 84 JF - Experimental biology and medicine (Maywood, N.J.) JO - Exp. Biol. Med. (Maywood) VL - 232 IS - 3 N2 - Endothelin-1 (ET-1) is a potent mitogen for many cells, especially when its levels are elevated under pathological conditions, as seen in tumor cell progression and astroglial activation in neuropathies. While ET-1 is known to cause astroglial proliferation, in the present study, multiple signaling pathways involved in ET-1-mediated astrocyte proliferation were characterized. Treatment with PD98059 and U0126 (MEK inhibitors) inhibited not only ET-1-induced cell proliferation but also ET-1-activated phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) in U373MG astrocytoma cells. Whereas the nonselective protein kinase C (PKC) inhibitor chelerythrine attenuated ET-1-induced cell proliferation, it was unable to block ET-1-induced ERK phosphorylation. However, ET-1 did not activate conventional or novel PKCs and did not elevate intracellular calcium. In addition, U73122 (a selective phospholipase C inhibitor), FTI-277 (an H-Ras inhibitor), as well as protein tyrosine kinase inhibitors also did not abolish ET-1-induced ERK1/2 phosphorylation. ET-1 treatment increased the activity of total Ras but not H-Ras. The phosphoinositide 3-kinase (PI3K) pathway appeared to be involved in signal transduction induced by ET-1, but it did not appear to participate in cross talk with the mitogen-activated protein kinase (MAPK) pathway. Activated ET receptors did not propagate signals either through protein tyrosine kinases or transactivation of EGF receptor tyrosine kinases, which typically trigger Ras-Raf-MAPK pathways. The results indicate that ET-1 stimulates cell proliferation by the activation of MAPK-, PKC-, and PI3K-dependent pathways that appear to function in a parallel manner. There is no apparent, direct "cross talk" between these pathways in U373MG cells, but rather, they might act on the independent but necessary components of the mitogenic effects of ET-1. SN - 1535-3702 UR - https://www.unboundmedicine.com/medline/citation/17327470/Parallel_signaling_pathways_in_endothelin_1_induced_proliferation_of_U373MG_astrocytoma_cells_ DB - PRIME DP - Unbound Medicine ER -