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Expression of RND Proteins in Human Myometrium¹

Division of Obstetrics and Gynaecology,³ Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Clinical Sciences at South Bristol, University of Bristol, Bristol, BS1 3NY, United Kingdom Department of Biochemistry,⁴ School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, United Kingdom Department of Pathology,⁵ Bristol Royal Infirmary, University of Bristol, Bristol, BS2 8HW, United Kingdom

ABSTRACT

RHO GTPases are key regulators of the actin cytoskeleton and stress fiber formation. In the human uterus, activated RHOA forms a complex with RHO-associated protein kinase (ROCK) which inhibits myosin light chain phosphatase (PPP1R12A), causing a calcium-independent increase in myosin light chain phosphorylation and tension (Ca²⁺ sensitization). Recently discovered small GTP binding RND proteins can inhibit RHOA and ROCK interaction to reduce calcium sensitization. Very little is known about the expression of RND proteins in the human uterus. We tested the hypothesis that the uterine quiescence observed during gestation is mediated by an increase in RND protein expression inhibiting RHOA–ROCK-mediated PPP1R12A phosphorylation. Immunohistochemistry and immunoblotting were used to determine RHOA and RND protein expression and localization in nonpregnant, pregnant nonlaboring, and laboring patients at term and patients in spontaneous preterm labor. Changes in protein expression estimated by densitometry between different patient groups were measured. A significant increase of RND2 and RND3 protein expression was observed in pregnant relative to nonpregnant myometrium associated with a loss of PPP1R12A phosphorylation. RND transfected myometrial cells demonstrated a dramatic loss of stress fiber formation and a "rounding" phenotype. RND upregulation in pregnancy may inhibit RHOA–ROCK-mediated increase in calcium sensitization to facilitate the uterine quiescence observed during gestation.

female reproductive tract, mechanisms of hormone action, parturition, pregnancy, RHOA, RND proteins, uterine quiescence, uterus

¹ Supported by a WellBeing of Women (Royal College of Obstetricians and Gynaecologists) Research Training Fellowship to J.L.

² Correspondence: FAX: 44 117 928 5290; A.LopezBernal{at}bristol.ac.uk

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