Uterine endoplasmic reticulum stress-unfolded protein response regulation of gestational length is caspase-3 and -7-dependent.
We previously identified myometrial caspase-3 (CASP3) as a potential regulator of uterine quiescence. We also determined that during pregnancy, the functional activation of uterine CASP3 is likely governed by an integrated endoplasmic reticulum stress response (ERSR) and is consequently limited by an increased unfolded protein response (UPR). The present study examined the functional relevance of uterine UPR-ERSR in maintaining myometrial quiescence and regulating the timing of parturition. In vitro analysis of the human uterine myocyte hTERT-HM cell line revealed that tunicamycin (TM)-induced ERSR modified uterine myocyte contractile responsiveness. Accordingly, alteration of in vivo uterine UPR-ERSR using a pregnant mouse model significantly modified gestational length. We determined that "normal" gestational activation of the ERSR-induced CASP3 and caspase 7 (CASP7) maintains uterine quiescence through previously unidentified proteolytic targeting of the gap junction protein, alpha 1(GJA1); however, surprisingly, TM-induced uterine ERSR triggered an exaggerated UPR that eliminated uterine CASP3 and 7 tocolytic action precociously. These events allowed for a premature increase in myometrial GJA1 levels, elevated contractile responsiveness, and the onset of preterm labor. Importantly, a successful reversal of the magnified ERSR-induced preterm birth phenotype could be achieved by pretreatment with 4-phenylbutrate, a chaperone protein mimic.
Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI 48201; Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201;
Chandrashekara
C
Kyathanahalli
Department of Obstetrics and Gynecology, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213;
Kenna
K
Organ
Department of Obstetrics and Gynecology, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213;
Rebecca S
RS
Moreci
Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI 48201; Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201;
Prashanth
P
Anamthathmakula
Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI 48201; Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201; Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
Sonia S
SS
Hassan
Department of Obstetrics and Gynecology, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213;
Steve N
SN
Caritis
Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI 48201; Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201; Department of Obstetrics and Gynecology, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213; Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
Pancharatnam
P
Jeyasuria
Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, MI 48201; Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48201; Department of Obstetrics and Gynecology, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213; Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892 jcondon@med.wayne.edu.
Jennifer C
JC
Condon
D000704:Analysis of Variance; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009215:Myometrium / Q000502:physiology*; D010654:Phenylbutyrates / Q000494:pharmacology; D011247:Pregnancy / Q000187:drug effects / Q000502:physiology*; D011374:Progesterone / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056811:Unfolded Protein Response / Q000502:physiology*; D014599:Uterus / Q000378:metabolism*
D017931:DNA Primers; D010654:Phenylbutyrates; D011374:Progesterone; C075773:4-phenylbutyric acid; D053148:Caspase 3; D053179:Caspase 7
caspase-3 and -7; endoplasmic reticulum stress; preterm labor; unfolded protein response; uterus