Steroid Receptor RNA Activator Stimulates Proliferation as Well as Apoptosis In Vivo

Abstract

Steroid receptor RNA activator (SRA) is an RNA that coactivates steroid hormone receptor-mediated transcription in vitro. Its expression is strongly up-regulated in many human tumors of the breast, uterus, and ovary, suggesting a potential role in pathogenesis. To assess SRA function in vivo, a transgenic-mouse model was generated to enable robust human SRA expression by using the transcriptional activity of the mouse mammary tumor virus long terminal repeat. Transgenic SRA was expressed in the nuclei of luminal epithelial cells of the mammary gland and tissues of the male accessory sex glands. Distinctive evidence for SRA function in vivo was obtained from the elevated levels of estrogen-controlled expression of progesterone receptor in transgenic mammary glands. Although overexpression of SRA showed strong promoting activities on cellular proliferation and differentiation, no alterations progressed to malignancy. Epithelial hyperplasia was accompanied by increased apoptosis, and preneoplastic lesions were cleared by focal degenerative transformations. In bitransgenic mice, SRA also antagonized ras-induced tumor formation. This work indicates that although coactivation of steroid-dependent transcription by SRA is accompanied by a proliferative response, overexpression is not in itself sufficient to induce turmorigenesis. Our results underline an intricate relationship between the different physiological roles of steroid receptors in conjunction with the RNA activator in the regulation of development, tissue homeostasis, and reproduction.Cancer is still a major cause of morbidity in humans due to the limited arsenal of therapies available. This lack of treatment options reflects a dearth in both general and specific scientific knowledge of tumorigenesis that exists largely because we still have not identified all the key molecular players responsible for controlled gene expression.We have previously reported the isolation and functional characterization of a novel transcriptional coactivator, steroid receptor RNA activator (SRA) (18). SRA acts as an RNA transcript by regulating eukaryotic gene expression mediated by the steroid receptors (SRs), which play critical roles in eukaryotic development, metabolism, reproduction, and disease (23, 45). In mammalian tissue culture cells, recombinant SRA showed potent coactivation activity with the receptors for androgens (AR), estrogens (ER), glucocorticoids, and progestins (PR). However, no evidence has yet been obtained for a direct binding of SRA to SRs. We found SRA in a protein complex together with SRC coactivators and therefore proposed that SRA-containing ribonucleoprotein complexes accentuate transcriptional specificity by integrating coregulator activities upon selective binding to SRs (18). Endorsing this model, SRA was shown to associate with the DEAD box proteins p72/p68 to act as an ER␣-specific ribonucleoprotein coactivator complex, which stimulates the amino-terminal activation domain of the receptor while concurrently integrating SRC/p160-mediated AF2 coa...

HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy

“…It has been reported that therapeutic administration of CD34 + cells has been shown to improve LVEF after experimental myocardial infarction . SRA1 is also known to stimulate proliferation as well as apoptosis in vivo (Lanz et al 2003). Taken together, all three genes appear to be important for cell proliferation or act as cell survival mediators and provide a novel mechanism contributing to heart failure.…”

The protein encoded by the functional steroid receptor RNA activator is a new modulator of ER alpha transcriptional activity

“…In vivo experiments showed that a decrease in SRA expression lead to a phenotype of myocardial contractile dysfunction in a zebrafish model [6], whereas an increase in mouse mammary gland stimulated proliferation and apoptosis [7]. Altogether, SRA is suspected to participate in normal and pathological events such as tissue differentiation and tumorigenesis.…”

The steroid receptor RNA activator protein (SRAP) controls cancer cell migration/motility

“…Since then, many studies have investigated the mechanisms of action of this functional RNA [2][3][4][5][6][7][8]. Through its core sequence (corresponding to exons 2-3-4 and part of exon 5), SRA behaves as a scaffold molecule that physically interacts with a number of RNA binding proteins and transcription factors via specific and critical secondary RNA structures [1][2][3][4]9].…”

“…Since then, many studies have investigated the mechanisms of action of this functional RNA [2][3][4][5][6][7][8]. Through its core sequence (corresponding to exons 2-3-4 and part of exon 5), SRA behaves as a scaffold molecule that physically interacts with a number of RNA binding proteins and transcription factors via specific and critical secondary RNA structures [1][2][3][4]9]. These SRA-containing complexes involve a wide range of molecules including, but not limited to, multiple nuclear receptors, nuclear receptor co-regulators, and proteins involved in gene silencing and gene insulation [2,3,8,[10][11][12][13].…”

“…These SRA-containing complexes involve a wide range of molecules including, but not limited to, multiple nuclear receptors, nuclear receptor co-regulators, and proteins involved in gene silencing and gene insulation [2,3,8,[10][11][12][13]. SRA therefore is believed to be a major transcriptional regulator potentially involved in numerous mechanisms including myogenesis, glucose uptake, tumorigenesis and tumor progression [4,6,[14][15][16][17].…”