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.

[1]  Jennifer A. Mitchell,et al.  Differential Expression of Activator Protein-1 Transcription Factors in Pregnant Rat Myometrium1 , 2002, Biology of reproduction.

[2]  Mingyao Liu,et al.  Regulation of c-fos expression by static stretch in rat myometrial smooth muscle cells. , 2002, American journal of obstetrics and gynecology.

[3]  B. Wung,et al.  Sequential Activation of Protein Kinase C (PKC)-α and PKC-ε Contributes to Sustained Raf/ERK1/2 Activation in Endothelial Cells under Mechanical Strain* , 2001, The Journal of Biological Chemistry.

[4]  B. Richardson,et al.  The risks of spontaneous preterm delivery and perinatal mortality in relation to size at birth according to fetal versus neonatal growth standards. , 2001, American journal of obstetrics and gynecology.

[5]  V. Gahtan,et al.  Role of mitogen-activated protein kinases in pulmonary endothelial cells exposed to cyclic strain. , 2000, Journal of applied physiology.

[6]  J. Frangos,et al.  Temporal gradient in shear-induced signaling pathway: involvement of MAP kinase, c-fos, and connexin43. , 2000, American journal of physiology. Heart and circulatory physiology.

[7]  H. Ueno,et al.  Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor. , 2000, American journal of physiology. Heart and circulatory physiology.

[8]  S. Chien,et al.  Sustained JNK activation induces endothelial apoptosis: studies with colchicine and shear stress. , 1999, American journal of physiology. Heart and circulatory physiology.

[9]  Qingbo Xu,et al.  Cyclic Strain Stress-induced Mitogen-activated Protein Kinase (MAPK) Phosphatase 1 Expression in Vascular Smooth Muscle Cells Is Regulated by Ras/Rac-MAPK Pathways* , 1999, The Journal of Biological Chemistry.

[10]  Shu Chien,et al.  Mechanotransduction in Response to Shear Stress , 1999, The Journal of Biological Chemistry.

[11]  S. Ogawa,et al.  Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. , 1999, Circulation research.

[12]  Y. Yazaki,et al.  Pulsatile stretch activates mitogen-activated protein kinase (MAPK) family members and focal adhesion kinase (p125(FAK)) in cultured rat cardiac myocytes. , 1999, Biochemical and biophysical research communications.

[13]  Y. Zou,et al.  Rho family small G proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiac myocytes. , 1999, Circulation research.

[14]  M. Haneda,et al.  Stretch-induced overproduction of fibronectin in mesangial cells is mediated by the activation of mitogen-activated protein kinase. , 1999, Diabetes.

[15]  K. Thai,et al.  Activation of mesangial cell signaling cascades in response to mechanical strain. , 1999, Kidney international.

[16]  S. Lye,et al.  Increased expression of the rat myometrial oxytocin receptor messenger ribonucleic acid during labor requires both mechanical and hormonal signals. , 1998, Biology of reproduction.

[17]  H. Jo,et al.  Phosphatidylinositol 3-kinase γ mediates shear stress-dependent activation of JNK in endothelial cells. , 1998, American journal of physiology. Heart and circulatory physiology.

[18]  Qingbo Xu,et al.  Activation of PDGF receptor α in vascular smooth muscle cells by mechanical stress , 1998 .

[19]  T. Tan,et al.  Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin , 1998, Oncogene.

[20]  M. Matsuzaki,et al.  Applied Pressure Enhances Cell Proliferation through Mitogen-activated Protein Kinase Activation in Mesangial Cells* , 1998, The Journal of Biological Chemistry.

[21]  A. Sharrocks,et al.  Differential targeting of MAP kinases to the ETS‐domain transcription factor Elk‐1 , 1998, The EMBO journal.

[22]  S. Chien,et al.  Shear stress activates p60src-Ras-MAPK signaling pathways in vascular endothelial cells. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[23]  S. Lye,et al.  Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. , 1997, Endocrinology.

[24]  Steven A. Carr,et al.  Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site* , 1997, The Journal of Biological Chemistry.

[25]  B. Sumpio,et al.  Activation of the adenylyl cyclase/cyclic AMP/protein kinase A pathway in endothelial cells exposed to cyclic strain. , 1997, Experimental cell research.

[26]  K. Sipos,et al.  Differential Effect of Shear Stress on Extracellular Signal-regulated Kinase and N-terminal Jun Kinase in Endothelial Cells , 1997, The Journal of Biological Chemistry.

[27]  Jiahuai Han,et al.  The primary structure of p38 gamma: a new member of p38 group of MAP kinases. , 1996, Biochemical and biophysical research communications.

[28]  R. Davis,et al.  Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways , 1996, Journal of Molecular Medicine.

[29]  J. Frangos,et al.  Fluid flow rapidly activates G proteins in human endothelial cells. Involvement of G proteins in mechanochemical signal transduction. , 1996, Circulation research.

[30]  A. Tanswell,et al.  Mechanical Strain Induces pp60 Activation and Translocation to Cytoskeleton in Fetal Rat Lung Cells (*) , 1996, The Journal of Biological Chemistry.

[31]  T. Peterson,et al.  Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells. , 1995, Circulation research.

[32]  A. Bridges,et al.  A synthetic inhibitor of the mitogen-activated protein kinase cascade. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Lye,et al.  Increase in messenger ribonucleic acid encoding the myometrial gap junction protein, connexin-43, requires protein synthesis and is associated with increased expression of the activator protein-1, c-fos. , 1995, Endocrinology.

[34]  J. Morrison,et al.  Amniotic Fluid Volume of Third‐Trimester Diamniotic Twin Pregnancies , 1995, Obstetrics and gynecology.

[35]  R. Goldenberg,et al.  The Origin and Outcome of Preterm Twin Pregnancies , 1995, Obstetrics and gynecology.

[36]  M. Persanti.  Increase in mRNA encoding the myometrial gap junction protein, connexin-43, requires protein synthesis and is associated with increased expression of the AP-1 protein, C-FOS , 1995 .

[37]  Richard J Smeyne,et al.  Regulation of c-fos expression in transgenic mice requires multiple interdependent transcription control elements , 1995, Neuron.

[38]  J. Inazawa,et al.  Structural organization of the human oxytocin receptor gene. , 1994, The Journal of biological chemistry.

[39]  J. Sadoshima,et al.  Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. , 1993, The EMBO journal.

[40]  C. Rodeck,et al.  Normal amniotic pressure throughout gestation , 1992, British journal of obstetrics and gynaecology.

[41]  L. Hill,et al.  Polyhydramnios: Ultrasonically Detected Prevalence and Neonatal Outcome , 1987, Obstetrics and gynecology.

[42]  T. Aso,et al.  Plasma levels of 13,14-dihydro-15-keto prostaglandin F2 alpha, estrogens, and progesterone during stretch-induced labor at term. , 1985, Prostaglandins.

[43]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[44]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[45]  S. Lye,et al.  Focal Adhesion Signaling in the Rat Myometrium Is Abruptly Terminated with the Onset of Labor1. , 2000, Endocrinology.

[46]  S. Lye,et al.  Myometrial transcriptional regulation of the gap junction gene, connexin-43. , 1995, Reproduction, fertility, and development.

[47]  J. D. Neill,et al.  The Physiology of reproduction , 1988 .

[48]  P. Mollard,et al.  Electrophysiological characterization of single pregnant rat myometrial cells in short-term primary culture. , 1986, The American journal of physiology.