Ligand-independent activation of steroid hormone receptors

Weigel, Nancy L.; Zhang, Yixian

doi:10.1007/s001090050241

Cited by 310 publications

(167 citation statements)

References 79 publications

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“…A recent publication has reported negative regulation of the interleukin (IL)-6 gene by GR in the absence of ligand (25), but this effect is dependent on TNF-a and is thus not a constitutive change as we have observed. Indeed, reports of ligand-independent activation by other steroid hormone receptors have typically been in response to other stimuli (49). Our studies indicate that unliganded GR is recruited to promoters through its interaction with GABP.…”

Section: -Hc +Hcmentioning

confidence: 55%

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

Ritter

Antonova

Mueller

2012

Molecular Cancer Research

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Loss of BRCA1 tumor suppressor function is a critical event in breast tumorigenesis. We have previously identified the stress hormone hydrocortisone as a negative regulator of BRCA1 expression in nonmalignant mammary cells. Here, we have identified a direct role for the unliganded glucocorticoid receptor (GR) in BRCA1 upregulation in the absence of hydrocortisone. The positive regulatory effect of GR is lost upon the addition of hydrocortisone. We have shown that GR interacts with the BRCA1 promoter only in the absence of hydrocortisone, and that this interaction is mediated through the b-subunit of the ets transcription factor GA-binding protein (GABP) at the RIBS promoter element. GR and GABPb interact in both coimmunoprecipitation and mammalian two-hybrid assays, and this interaction involves the N-terminal to central regions of both proteins. This work presents the first evidence of a ligand-independent role for GR as a positive regulator of gene expression, and loss of GR from the BRCA1 promoter in response to stress hormones leads to decreased BRCA1 expression. Because low levels of BRCA1 have been implicated in the development of sporadic breast cancer, this may represent a novel mechanism through which prolonged stress signaling increases breast cancer risk. Mol Cancer Res; 10(4); 558-69. Ó2012 AACR. IntroductionGerm line mutations in the BRCA1 tumor suppressor contribute to familial breast tumor formation but BRCA1 mutations do not seem to occur in sporadic breast cancer tumors (1). Instead, sporadic breast tumors exhibit decreased levels of BRCA1 expression, and the degree of downregulation seems to be correlated with tumor grade, rate of tumor progression, and risk of metastasis (2-6). This implies that loss of BRCA1 function, either through decreased activity or downregulation of expression, is a critical event in the etiology of breast cancer. Phenotypically normal breast epithelial cells from individuals harboring a BRCA1 germ line mutation (a so called "one-hit" mutation accompanied by a 50% decrease in BRCA1 function) express an altered mRNA profile compared with normal cells from individuals without a BRCA1 mutation (7). This suggests that decreases in functional BRCA1

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Section: -Hc +Hcmentioning

confidence: 55%

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

Ritter

Antonova

Mueller

2012

Molecular Cancer Research

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“…Most of the ERa coactivators binding to the AF-2 region of ERa have been shown to increase ERa transcriptional activity in a ligand-dependent manner. Recently, a few coactivators interact with the AF-1 or DBD region and regulate ERa transcriptional activity in a ligand-independent manner (Chakravarti et al, 1996;Yao et al, 1996;Weigel and Zhang, 1998;Alen et al, 1999;Endoh et al, 1999;Xu et al, 1999;Ding et al, 2003). Given that c-Abl does not interact with ERa P79,333A, the ligand-independent ERa transactivation by c-Abl seems to involve the AF-1 and AF-2 domains, especially the AF1 domain.…”

Section: Discussionmentioning

confidence: 99%

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

He¹,

Zheng²,

Song³

et al. 2010

Oncogene

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Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligandactivated transcription factors. Similar to other steroid hormone receptors, estrogen receptor a (ERa) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERa associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERa and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERa can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERa phosphorylation by c-Abl stabilizes ERa, resulting in enhanced ERa transcriptional activity and increased expression of endogenous ERa target genes. Furthermore, ERa phosphorylation at the Y-219 site affects DNA binding and dimerization by ERa. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Ablinduced accumulation of ERa and enhancement of ERa transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERa function. Moreover, the ERa (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERa expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.

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“…The two regions present in ERs that contribute to transcriptional activity are called activation functions (AFs). AF-1 is located in the N-terminal region and could be activated even in a ligand-independent manner depending on the phosphorylation status of ER (Bunone et al, 1996;Weigel and Zhang, 1998;Tremblay et al, 1999); AF-2 is present at the C-terminus and shows a ligand-dependent activation (Weihua et al, 2003;Wrenn and Katzenellenbogen, 1993).…”

Section: Mechanisms Of Estrogen Effects Mechanisms Of Estrogen Effectmentioning

confidence: 99%

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

Galluzzo

Marino

2006

Genes Nutr

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Ligand-independent activation of steroid hormone receptors

Cited by 310 publications

References 79 publications

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

The Unliganded Glucocorticoid Receptor Positively Regulates the Tumor Suppressor GeneBRCA1through GABP Beta

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

Nutritional flavonoids impact on nuclear and extranuclear estrogen receptor activities

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