The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by alpha-T-catenin upregulation.
By using complementary in vitro and ex vivo approaches, we show that the risk allele (Y153H) of the pre-eclampsia susceptibility gene STOX1 negatively regulates trophoblast invasion by upregulation of the cell-cell adhesion protein alpha-T-catenin (CTNNA3). This is effectuated at the crucial epithelial-mesenchymal transition of proliferative into invasive extravillous trophoblast. This STOX1-CTNNA3 interaction is direct and includes Akt-mediated phosphorylated control of nucleo-cytoplasmic shuttling and ubiquitin-mediated degradation as shared with the FOX multigene family. This, to our knowledge, is the first time a genotype associated with pre-eclampsia has been shown to directly limit first trimester extravillous trophoblast invasion, the earliest hallmark of pre-eclampsia.
van Dijk
Marie
M
Department of Clinical Chemistry, VU University Medical Center, Amsterdam the Netherlands. m.vdijk@vumc.nl
van Bezu
Jan
J
van Abel
Daan
D
Dunk
Caroline
C
Blankenstein
Marinus A
MA
Oudejans
Cees B M
CB
Lye
Stephen J
SJ
D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D051178:alpha Catenin / Q000378:metabolism*
C441963:CTNNA3 protein, human; D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; C500784:STOX1 protein, human; D051178:alpha Catenin; D051057:Proto-Oncogene Proteins c-akt