A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Nature medicine (Impact Factor: 27.36). 06/2012; 18(7):1102-11. DOI: 10.1038/nm.2826
Source: PubMed


Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1-null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf⁻/⁻ and Mmp9⁻/⁻ mice with surgically induced endometriosis showed that activation of tumor necrosis factor a (TNF-α)-induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α-mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α-MMP9-SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.

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    • "SRC-3Δ4 is a splice isoform of SRC-3 with a deletion of exon 4 (SRC-3Δ4) and the protein lacks the N-terminal bHLH (helix-loopl-helix) domain that contains a nuclear localization signal (NLS) (Long, et al. 2010, Reiter, et al. 2001). More recently, a shorter 70kD isoform of SRC-1 was identified and found to be highly elevated in human and mouse endometriotic tissues (Han, et al. 2012). This 70kD isoform of SRC-1 is the C-terminal fragment of the full-length SRC-1which is proteolytically cleaved by MMP-9. "
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    ABSTRACT: Transcriptional coactivators have evolved as an important new class of functional proteins that participate with virtually all transcription factors and NRs to intricately regulate gene expression in response to a wide variety of environmental cues. Recent findings have highlighted that coactivators are important for almost all biological functions, and consequently, genetic defects can lead to severe pathologies. Drug discovery efforts targeting coactivators may prove valuable for treatment of a variety of diseases.
    Full-text · Article · Jul 2014 · Journal of Molecular Endocrinology
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    • "Given their diverse coregulator properties, it is not surprising that dysregulation of SRC expression levels has been causally linked to numerous clinicopathologies, ranging from cancers of the breast and prostate to metabolic dysfunction and endometriosis [3]–[9]. Along with clinical data, knockout mouse models for each SRC (or combinations thereof) have been routinely used to support coregulator involvement in both the normal function and etiopathogenesis of a given target tissue [10]–[16]. "
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    ABSTRACT: As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Possible signaling pathways in human endo- metriosis The exact role of the peritoneum in the establishment and maintenance of endometriosis has been elusive, as recently reviewed [4]. Multiple molecules and signaling pathways have been speculated to participate in the pathogenic progression of endometriosis lesions [3] [4] [5] [7], including 17β-hydroxysteroid- dehydrogenases [67] [68], steroid receptor coactivator-1 [69], adhesion/attachment/invasion proteins [70] [71], disintegrin and metalloproteinases [72], nuclear factor-kappa B [73], Wnt/β-catenin [74], and the mitogen-activated protein kinase and phosphatidylinositol 3'-kina- se/AKT [75] signaling pathways. These molecules and signaling pathways are either directly linked to estrogen synthesis and ER and PR activation or interact with ER and PR signaling pathways at different levels through signaling molecules downstream of the receptor. "
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    ABSTRACT: Endometriosis is a complex and challenging disease that involves aberrant adhesion, growth, and progression of endometrial tissues outside of the uterine cavity, and there is evidence to suggest that estrogen plays a key role in its development and progression. Numerous in vivo clinical studies have described the ectopic expression and regulation of estrogen receptor (ER) and progesterone receptor (PR) in the different types of endometriosis compared to normal or eutopic endometrium. However, we have noticed that conflicting and contradictory results have been presented in terms of ER subtype (ERα and ERβ) and PR isoform (PRA and PRB) expression. Both ER and PR are transcription factors and ER/PR-mediated responses depend on the coordinated, opposing, and compensatory functions of ER subtypes and PR isoforms. Moreover, analysis of the uterine phenotypes of ERα/ERβ and PRA/PRB knockout mice indicates that different ER subtypes and PR isoforms mediate distinct responses to steroid hormones and play different roles in uterine function. In this review, we outline studies that have elucidated the molecules and signaling pathways that are linked to ER and/or PR signaling pathways in the development and progression of endometriosis.
    Full-text · Article · Feb 2014 · American Journal of Translational Research
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