Abstract
To understand the mechanisms of prostaglandin F2alpha (PGF2alpha)-induced protein synthesis in vascular smooth muscle cells (VSMC), we have studied its effect on two major signal transduction pathways: mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI3-kinase) and their downstream targets ribosomal protein S6 kinase (p70(S6k)) and eukaryotic initiation factor eIF4E and its regulator 4E-BP1. PGF2alpha induced the activities of extracellular signal-regulated kinase 2 (ERK2) and Jun N-terminal kinase 1 (JNK1) groups of mitogen-activated protein kinases, PI3-kinase, and p70(S6k) in a time-dependent manner in growth-arrested VSMC. PGF2alpha also induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis, and basic fibroblast growth factor-2 (bFGF-2) expression in VSMC. Whereas inhibition of PI3-kinase by wortmannin completely blocked the p70(S6k) activation, it only partially decreased the ERK2 activity, and had no significant effect on global protein synthesis and bFGF-2 expression induced by PGF2alpha. Rapamycin, a potent inhibitor of p70(S6k), also failed to prevent PGF2alpha-induced global protein synthesis and bFGF-2 expression, although it partially decreased ERK2 activity. In contrast, inhibition of ERK2 activity by PD 098059 led to a significant loss of PGF2alpha-induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis, and bFGF-2 expression. PGF2alpha-induced phosphorylation of eIF4E and 4E-BP1 was also found to be sensitive to inhibition by both wortmannin and rapamycin. These findings demonstrate that 1) PI3-kinase-dependent and independent mechanisms appear to be involved in PGF2alpha-induced activation of ERK2; 2) PGF2alpha-induced eIF4E and 4E-BP1 phosphorylation appear to be mediated by both ERK-dependent and PI3-kinase-dependent rapamycin-sensitive mechanisms; and 3) ERK-dependent eIF4E phosphorylation but not PI3-kinase-dependent p70(S6k) activation correlates with PGF2alpha-induced global protein synthesis and bFGF-2 expression in VSMC.
Highlights
From the Division of Cardiology, University of Texas Medical Branch, Galveston, Texas 77555, the §Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada, and ¶Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
To understand the mechanisms of prostaglandin F2␣ (PGF2␣)-induced protein synthesis in vascular smooth muscle cells (VSMC), we have studied its effect on two major signal transduction pathways: mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI3kinase) and their downstream targets ribosomal protein S6 kinase (p70S6k) and eukaryotic initiation factor eIF4E and its regulator 4E-BP1
These findings demonstrate that 1) PI3-kinase-dependent and independent mechanisms appear to be involved in PGF2␣-induced activation of ERK2; 2) PGF2␣-induced eIF4E and 4E-BP1 phosphorylation appear to be mediated by both ERK-dependent and PI3-kinase-dependent rapamycin-sensitive mechanisms; and 3) ERK-dependent eIF4E phosphorylation but not PI3-kinase-dependent p70S6k activation correlates with PGF2␣-induced global protein synthesis and bFGF-2 expression in Vascular smooth muscle cell (VSMC)
Summary
From the Division of Cardiology, University of Texas Medical Branch, Galveston, Texas 77555, the §Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada, and ¶Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709. To understand the mechanisms of prostaglandin F2␣ (PGF2␣)-induced protein synthesis in vascular smooth muscle cells (VSMC), we have studied its effect on two major signal transduction pathways: mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI3kinase) and their downstream targets ribosomal protein S6 kinase (p70S6k) and eukaryotic initiation factor eIF4E and its regulator 4E-BP1. Several studies have reported that phosphatidylinositol 3-kinase (PI3-kinase) plays a role in the activation of p70S6k in response to a variety of mitogens (10 –12) Another event that is critical in the regulation of protein synthesis is the binding of mRNA to ribosomes, which is facilitated by a translation initiation complex, eIF4F [1,2,3,4]. The purpose of the present study is to investigate the signaling events that are evoked in response to
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
