Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells.
Evidence indicates that stretch of the uterus imposed by the growing fetus contributes to the onset of labor. Previously we have shown that mechanically stretching rat myometrial smooth muscle cells (SMCs) induces c-fos expression. To investigate this stretch-induced signaling, we examined the involvement of the mitogen-activated protein kinase (MAPK) family. We show that stretching rat myometrial SMCs induces a rapid and transient phosphorylation (activation) of MAPKs: extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38. The use of selective inhibitors for the ERK pathway (PD-98059 and U-0126), p38 (SB-203580), and JNK pathway (curcumin) demonstrated that activation of all three MAPK signaling pathways was necessary for optimal stretch-induced c-fos expression. We also demonstrate that upstream tyrosine kinase activity is involved in the mechanotransduction pathway leading to stretch-induced MAPK activation and c-fos mRNA expression. To further examine the role of MAPKs in vivo, we used a unilaterally pregnant rat model. MAPKs (ERK and p38) are expressed in the pregnant rat myometrium with maximal ERK and p38 phosphorylation occurring in the 24 h immediately preceding labor. Importantly, the rise in MAPK phosphorylation was confined to the gravid horn and was absent in the empty uterine horn, suggesting that mechanical strain imposed by the growing fetus controls MAPK activation in the myometrium. Collectively, this data indicate that mechanical stretch modulates MAPK activity in the myometrium leading to c-fos expression.
Oldenhof
Alexandra D
AD
Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario.
Shynlova
Oksana P
OP
Liu
Mingyao
M
Langille
B Lowell
BL
Lye
Stephen J
SJ
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000201:enzymology*; D009215:Myometrium / Q000166:cytology / Q000201:enzymology*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011247:Pregnancy; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D014590:Uterine Contraction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; C113580:U 0126; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003474:Curcumin; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one