Biol Reprod Keystone Symposia Conference on Frontiers in Reproductive Biology & Regulation of Fertility.
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BOR - Papers in Press, published online ahead of print February 14, 2007.
Biol Reprod 2007, 10.1095/biolreprod.106.058982
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Submitted November 14, 2006
Returned for revision November 30, 2006
Accepted February 2, 2007

Pregnancy


Up-Regulation of Myometrial RHO Effector Proteins (PKN1 and DIAPH1) and CPI-17 (PPP1R14A) Phosphorylation in Human Pregnancy Is Associated with Increased GTP-RHOA in Spontaneous Preterm Labor

J. Lartey *, M. Smith , J. Pawade , B. Strachan , H. Mellor , and A. López Bernal

* To whom correspondence should be addressed. E-mail: j.lartey{at}bris.ac.uk.

Abstract
RHO GTP binding proteins are important regulators of actin-myosin interaction in uterine smooth muscle cells. Active (GTP bound) RHOA binds to RHO-associated protein kinase (ROCK1) which inhibits the myosin binding subunit (PPP1R12A) of myosin light chain phosphatase leading to a calcium independent increase in myosin light chain phosphorylation and tension termed "calcium sensitisation." The RHO effector protein kinase N (PKN1) also increases calcium sensitization by phosphorylating the protein kinase C (PRKCB) dependent protein CPI-17 (PPP1R14A) to inhibit the PPP1c subunit of myosin phosphatase. Moreover other RHO proteins like RHOB, RHOD and their effectors (DIAPH1 and DIAPH2) may modulate PKN1/ ROCK1 signalling to effect changes in myosin phosphatase activity and myosin light chain phosphorylation. The increase in contractile activity observed in term and preterm labor may be due to an increase in RHO activity and/or changes in RHO related proteins. We found that RHOA and RHOB mRNA levels in myometrium were increased in pregnancy, but the expression of RHOA and RHOB proteins did not change with pregnancy or labor. GTP bound RHOA was increased in pregnancy and this increase was significant in spontaneous preterm labor myometrium. PKN1 expression and PPP1R14A phosphorylation were dramatically increased in pregnant myometrium. We also observed increases in DIAPH1 expression in spontaneous term and preterm labor myometrium. This study shows that human pregnancy is characterized by an increase in PKN1 expression and PPP1R14A phosphorylation in myometrium. Moreover, increases in GTP bound RHOA and DIAPH1 expression may contribute to the increase in uterine activity in idiopathic preterm labor.

Key words: Female Reproductive Tract • Pregnancy • Oxytocin • Parturition • Uterus


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F. Dabertrand, N. Fritz, J. Mironneau, N. Macrez, and J.-L. Morel
Role of RYR3 splice variants in calcium signaling in mouse nonpregnant and pregnant myometrium
Am J Physiol Cell Physiol, September 1, 2007; 293(3): C848 - C854.
[Abstract] [Full Text] [PDF]


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