Estrogen Opposes the Apoptotic Effects of Bone Morphogenetic Protein 7 on Tissue Remodeling

Abstract

Interactions between estrogen and growth factor signaling pathways at the level of gene expression play important roles in the function of reproductive tissues. For example, estrogen regulates transforming growth factor beta (TGF␤) in the uterus during the proliferative phase of the mammalian reproductive cycle. Bone morphogenetic protein 7 (BMP-7), a member of the TGF␤ superfamily, is also involved in the development and function of reproductive tissues. However, relatively few studies have addressed the expression of BMP-7 in reproductive tissues, and the role of BMP-7 remains unclear. As part of an ongoing effort to understand how estrogen represses gene expression and to study its interactions with other signaling pathways, chick BMP-7 (cBMP-7) was cloned. cBMP-7 mRNA levels are repressed threefold within 8 h following estrogen treatment in the chick oviduct, an extremely estrogen-responsive reproductive tissue. This regulation occurs at the transcriptional level. Estrogen has a protective role in many tissues, and withdrawal from estrogen often leads to tissue regression; however, the mechanisms mediating regression of the oviduct remain unknown. Terminal transferase-mediated end-labeling and DNA laddering assays demonstrated that regression of the oviduct during estrogen withdrawal involves apoptosis, which is a novel observation. cBMP-7 mRNA levels during estrogen withdrawal increase concurrently with the apoptotic index of the oviduct. Furthermore, addition of purified BMP-7 induces apoptosis in primary oviduct cells. This report demonstrates that the function of BMP-7 in the oviduct involves the induction of apoptosis and that estrogen plays an important role in opposing this function.

Analysis of spatial and temporal expression patterns of bone morphogenetic protein family members in the rat uterus over the estrous cycle

“…In a previous paper, Ozkaynak et al (1997) reported that administration of exogenous estradiol markedly inhibits uterine BMP-7 transcripts in vivo. Similarly, studies on the chick oviduct have demonstrated an inhibitory effect of estrogen on BMP-7 gene expression (Monroe et al 2000). Therefore, our finding that BMP-7 expression was not suppressed by increases in circulating estradiol levels during the estrous cycle was unexpected.…”

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

“…All primary microarray data are accessible at www.ncbi.nlm.nih.gov/geo (GSE7382). We selected BMP7 for further study because BMP7 mediates epithelial-mesenchymal signaling (Dean et al, 2004), and epithelial cell apoptosis and proliferation in several different organ systems (Luo et al, 1995;Monroe et al, 2000). Consistent with these observations, we found that BMP7 can decrease proliferation and increase apoptosis of normal and cancerous mammary epithelial cells (Supplementary Figure S8).…”

“…Estradiol has been shown to downregulate both BMP7 and its receptor ActRIIB in a variety of hormone-responsive epithelial cells (Kusumegi et al, 2004). In fact, estradiol inhibits apoptosis in epithelial cells of reproductive epithelia by suppressing BMP7 signaling (Monroe et al, 2000). Interestingly, estradiol completely inhibited LMO4-mediated apoptosis in MCF7 cells (Figure 3c).…”

Dynamic expression of bone morphogenetic protein 4 in reproductive organs of female mice

“…Exogenous treatment with estradiol has been shown to decrease expression of uterine Bmp7 mRNA in vivo (Ozkaynak et al 1997). Similarly, estradiol treatment has been shown to repress BMP7 mRNA levels in chicken oviduct (Monroe et al 2000). In addition, BMP7 is shown to regulate apoptosis in primary oviductal cells (Monroe et al 2000).…”