Estrogen-Induced Apoptosis by Inhibition of the Erythroid Transcription Factor GATA-1

Abstract

Steroid hormones regulate diverse biological functions, including programmed cell death (apoptosis).Although steroid receptors have been studied extensively, relatively little is known regarding the cellular targets through which apoptosis is triggered. We show here that the ligand-activated estrogen receptor (ER) induces apoptosis in an erythroid cell line by binding to, and consequently inhibiting the activity of, GATA-1, an erythroid transcription factor essential for the survival and maturation of erythroid precursor cells. GATA-1 inhibition is reflected in the downregulation of presumptive GATA-1 target genes. Constitutive overexpression of a GATA-binding protein resistant to the effects of the ER partially rescues ER-induced apoptosis. Induction of apoptosis by a mutant ER defective in binding to the estrogen response element but active in GATA-1 inhibition suggests that ER-mediated inhibition of GATA-1 is direct and does not require estrogen response element-dependent transcriptional activation. Thus, a lineage-restricted transcription factor, such as GATA-1, constitutes one cellular target through which steroid hormones may control apoptosis. As GATA-binding proteins are evolutionarily conserved, we speculate that members of the steroid receptor family may exert some of their diverse biological functions in different cellular contexts through interference with the function of GATA-binding proteins.

Estrogen and raloxifene induce apoptosis by activating p38 mitogen-activated protein kinase cascade in synthetic vascular smooth muscle cells

“…In the present study, we demonstrated that E 2 induced apoptosis through a p38 signaling cascade in synthetic VSMC. Although estrogen was reported to have an anti-apoptotic effect in vascular endothelial cells (Razandi et al 2000), it was reported that estrogen induced apoptosis in an erythroid cell line (Blobel & Orkin 1996) and induced apoptosis and G 1 cell cycle arrest of human multiple myeloma cells (Wang et al 2001). Moreover, E 2 stimulates the growth of MCF-7 cells and does not induce p38 phosphorylation or apoptosis, while activation of p38 by E 2 is coupled to ER-induced apoptosis in HeLa cells transfected with ER (Zhang & Shapiro 2000).…”

Transcription Factor GATA-4 Is Expressed in Pediatric Yolk Sac Tumors

“…It is of interest that recent data have linked GATAbinding proteins with antiapoptotic processes, which often operate in malignant cells. Specifically, down-regulation of GATA-1 is associated with apoptosis in proerythroblasts, 22 and decreased expression of GATA-4 is associated with cardiomyocyte death 9 and ovarian follicular atresia via apoptosis. 12 Although there are limited data on the molecular events leading to the formation of germ cell tumors, several molecules have been implicated in the pathophysiology of these tumors.…”

Role of specificity protein transcription factors in estrogen-induced gene expression in MCF-7 breast cancer cells

“…There is an increasing evidence that the classical genomic ER-ERE complex formation is only one of several genomic and non-genomic pathways of estrogen action (Blobel & Orkin 1996, Delfino & Walker 1999, Kelly & Wagner 1999, Kushner et al 2000, Watson et al 2002, Razandi et al 2004, Safe & Kim 2004, Levin 2005. Genomic ER associates with other transcription factors such as the activating protein-1 (AP-1) complex, nuclear factor kappa B (NFkB), and specificity proteins (Sps) to modulate ligand-dependent gene expression.…”