Transmembrane Mucin Expression and Function in Embryo Implantation and Placentation

Fig. 4.1
Structural representations of TMs. (a) MUC1, MUC4, MUC16 (not drawn to scale). Abbreviations: VNTR variable number of tandem repeats, SEA sea urchin sperm protein–enterokinase–agrin, TMD transmembrane domain, CT cytoplasmic tail, CysD Cys-rich domain, NIDO nidogen homology sequence, AMOP adhesion-associated domain, vWD von Willebrand factor D domain, EGF epidermal growth factor-like regions. (b) Size comparison of MUC1, extending 200–500 nm from the cell surface, and epidermal growth factor receptor (EGFR), 50 nm from the cell surface (drawn to scale)

4.3.2 Functions

4.4 Control of TM Expression

4.4.1 Cytokines

4.4.2 Steroid Hormones

4.4.3 PPARs and Trophoblastic Expression of MUC1

Studies in mice revealed two interesting features of Muc1 expression: (1) that another transcriptional coregulator, Peroxisome Proliferator-Activated Receptor-γ (PPARγ), stimulates Muc1 expression and (2) Muc1 is expressed by placental trophoblast (Shalom-Barak et al. 2004). PPARγ is activated by various natural ligands including certain polyunsaturated fatty acids and prostaglandin J2, as well as the synthetic thiazolidinediones, including rosiglitazone and pioglitazone. Investigation of PPARγ actions in human cell lines revealed an opposite response to that observed in mice, namely, inhibition with regard to both progesterone- (Wang et al. 2010) and EGF-simulated (Dharmaraj et al. 2013) MUC1 expression. The human MUC1 gene has a 21 bp insertion in the PPARγ-responsive region which appears to account for the differences in responsiveness between species. In addition to other actions, PPARγ and its agonists have anti-inflammatory actions (Kapadia et al. 2008). In this regard, PPARγ activators can inhibit cytokine-stimulated expression of all three TMs (Fig. 4.2). Therefore, it appears that TM expression can be regulated coordinately offering opportunities for broad therapeutic control. PPARγ activators have therapeutic value in placental dysfunction, including mitigation of symptoms associated with preeclampsia (McCarthy et al. 2011; Kadam et al. 2015). Whether this has relevance to reduction of trophoblast MUC1 expression is unclear.


Fig. 4.2
Coordinate regulation of TMs by cytokines and rosiglitazone. MCF7 cells were incubated for 48 h with vehicle control (V), rosiglitazone (100 μM; R), TNFα (25 ng/ml) plus IFNγ (200 IU) (T + I), or TNFα plus IFNγ plus rosiglitazone (T + I + R). RNA was extracted from triplicate independent samples in each case for qRT-PCR analyses of (a) MUC1, (b) MUC4, and (c) MUC16 mRNA relative to that of β-actin. *** p < 0.001 V vs. T + I and T + I + R, R vs. T + I and T + I + R

4.4.4 Sheddases

4.5 Transmembrane Mucin Binding Proteins

4.5.1 Galectins

4.5.2 Selectins

4.5.3 Siglecs

4.5.4 Mesothelin

4.5.5 TM Binding Signaling Proteins

4.6 Summary and Future Directions


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Oct 31, 2016 | Posted by in HEMATOLOGY | Comments Off on Transmembrane Mucin Expression and Function in Embryo Implantation and Placentation

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