PMID- 24586788
OWN - NLM
STAT- MEDLINE
DCOM- 20150113
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 2
DP  - 2014
TI  - The ubiquitin ligase ASB4 promotes trophoblast differentiation through the 
      degradation of ID2.
PG  - e89451
LID - 10.1371/journal.pone.0089451 [doi]
LID - e89451
AB  - Vascularization of the placenta is a critical developmental process that ensures 
      fetal viability. Although the vascular health of the placenta affects both 
      maternal and fetal well being, relatively little is known about the early stages 
      of placental vascular development. The ubiquitin ligase Ankyrin repeat, SOCS 
      box-containing 4 (ASB4) promotes embryonic stem cell differentiation to vascular 
      lineages and is highly expressed early in placental development. The 
      transcriptional regulator Inhibitor of DNA binding 2 (ID2) negatively regulates 
      vascular differentiation during development and is a target of many ubiquitin 
      ligases. Due to their overlapping spatiotemporal expression pattern in the 
      placenta and contrasting effects on vascular differentiation, we investigated 
      whether ASB4 regulates ID2 through its ligase activity in the placenta and 
      whether this activity mediates vascular differentiation. In mouse placentas, ASB4 
      expression is restricted to a subset of cells that express both stem cell and 
      endothelial markers. Placentas that lack Asb4 display immature vascular 
      patterning and retain expression of placental progenitor markers, including ID2 
      expression. Using JAR placental cells, we determined that ASB4 ubiquitinates and 
      represses ID2 expression in a proteasome-dependent fashion. Expression of ASB4 in 
      JAR cells and primary isolated trophoblast stem cells promotes the expression of 
      differentiation markers. In functional endothelial co-culture assays, JAR cells 
      ectopically expressing ASB4 increased endothelial cell turnover and stabilized 
      endothelial tube formation, both of which are hallmarks of vascular 
      differentiation within the placenta. Co-transfection of a degradation-resistant 
      Id2 mutant with Asb4 inhibits both differentiation and functional responses. 
      Lastly, deletion of Asb4 in mice induces a pathology that phenocopies human 
      pre-eclampsia, including hypertension and proteinuria in late-stage pregnant 
      females. These results indicate that ASB4 mediates vascular differentiation in 
      the placenta via its degradation of ID2.
FAU - Townley-Tilson, W H Davin
AU  - Townley-Tilson WH
AD  - McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel 
      Hill, North Carolina, United States of America ; Department of Cell Biology and 
      Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North 
      Carolina, United States of America.
FAU - Wu, Yaxu
AU  - Wu Y
AD  - McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel 
      Hill, North Carolina, United States of America.
FAU - Ferguson, James E 3rd
AU  - Ferguson JE 3rd
AD  - McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel 
      Hill, North Carolina, United States of America.
FAU - Patterson, Cam
AU  - Patterson C
AD  - McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel 
      Hill, North Carolina, United States of America ; Department of Cell Biology and 
      Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North 
      Carolina, United States of America.
LA  - eng
GR  - R01 HL061656/HL/NHLBI NIH HHS/United States
GR  - T32 HL069768/HL/NHLBI NIH HHS/United States
GR  - 5R01HL061656/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140221
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Asb4 protein, mouse)
RN  - 0 (Idb2 protein, mouse)
RN  - 0 (Inhibitor of Differentiation Protein 2)
RN  - 0 (Suppressor of Cytokine Signaling Proteins)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/*physiology
MH  - Cell Line, Tumor
MH  - Coculture Techniques
MH  - Female
MH  - Humans
MH  - Inhibitor of Differentiation Protein 2/genetics/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Placenta/metabolism
MH  - Placentation/*physiology
MH  - Pregnancy
MH  - Suppressor of Cytokine Signaling Proteins/genetics/*metabolism
MH  - Trophoblasts/cytology/*metabolism
PMC - PMC3931756
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/03/04 06:00
MHDA- 2015/01/15 06:00
PMCR- 2014/02/21
CRDT- 2014/03/04 06:00
PHST- 2013/10/31 00:00 [received]
PHST- 2014/01/21 00:00 [accepted]
PHST- 2014/03/04 06:00 [entrez]
PHST- 2014/03/04 06:00 [pubmed]
PHST- 2015/01/15 06:00 [medline]
PHST- 2014/02/21 00:00 [pmc-release]
AID - PONE-D-13-44733 [pii]
AID - 10.1371/journal.pone.0089451 [doi]
PST - epublish
SO  - PLoS One. 2014 Feb 21;9(2):e89451. doi: 10.1371/journal.pone.0089451. eCollection 
      2014.