Involvement of cyclin D3, CDKN1A (p21), and BIRC5 (Survivin) in interleukin 11 stimulation of decidualization in mice.
Interleukin 11 receptor alpha (Il11ra) null mice are infertile due to defective decidualization and abnormal trophoblast invasion. We have previously shown in these mice that downregulation of decidual proteinase inhibitors plays a role in uncontrolled trophoblast invasion. However, the decidua is abnormally smaller in pseudopregnant Il11ra null mice, where trophoblast invasion is not a factor. Here, we examined whether defective decidualization is due to dysregulation of key molecules involved in decidual cell growth and differentiation. We found a dramatic downregulation of cyclin D3 in Il11ra null mice. We also found that IL11 robustly stimulates the expression of cyclin D3 in cell culture. CDK4 and CDK6, known partners of cyclin D3, are not affected. Immunolocalization studies show absence of cyclin D3 in the mesometrial site and absence of differentiated polyploid cells in the antimesometrial site of Il11ra null mice. We also examined the expression of cell differentiation factors CDKN1A (p21) and CDKN1B (p27), and found that in both in vivo and cell culture the expression of CDKN1A (p21) but not CDKN1B (p27) is under the control of IL11. Another clear target of IL11 in the decidua is BIRC5 (Survivin), whose expression is repressed in the decidua of Il11ra null mice and stimulated by IL11 in cell culture. Taken together, these results provide, at least in part, an explanation for the defective small decidua of mice lacking the Il11ra gene, and reveal for the first time that cyclin D3, CDKN1A (p21), and BIRC5 (Survivin) are targets of IL11 in the decidua.
Li
Feixue
F
Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Devi
Y Sangeeta
YS
Bao
Lei
L
Mao
Jifang
J
Gibori
Geula
G
D000818:Animals; D002460:Cell Line; D056743:Cyclin D3; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D003656:Decidua / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D017370:Interleukin-11 / Q000494:pharmacology*; D053703:Interleukin-11 Receptor alpha Subunit / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin
C117749:Birc5 protein, mouse; C534697:Ccnd3 protein, mouse; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C508429:Il11ra1 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D012097:Repressor Proteins; D000077022:Survivin; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6