Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewThe emerging role of the transcriptional coregulator RIP140 in solid tumors☆
Introduction
The transcription cofactor RIP140 (receptor interacting protein, 140 kDa), also known as NRIP1 (nuclear receptor-interacting protein 1), was first identified in human cancer cells through its interaction with estrogen receptor α [1]. Later on, RIP140 was shown to interact with many other nuclear receptors and transcription factors (for a review see [2]). RIP140 mainly acts as a transcriptional repressor by means of four inhibitory domains that recruit histone deacetylases or C-terminal binding proteins [3], [4]. Several post-translational modifications, such as sumoylation and acetylation, play important roles in controlling the subcellular location and repressive activity of RIP140 (for a review see [5]). The RIP140 gene, located on chromosome 21 in human and 16 in mice, encompasses several exons spread over more than 100 kb with the whole coding sequence encoded by a single exon (Fig. 1A). Although, ubiquitously expressed (Fig. 1B), the RIP140 gene is finely regulated at the transcriptional and post-transcriptional levels [6], [7], [8].
The physiological importance of RIP140 has been evaluated using mice that lack the Rip140 gene (RIPKO mice). These animals are viable but display a wide range of phenotypic alterations in various tissues and organs such as infertility of female mice [9] or reduced body fat content [10] and, more recently, severe cognitive impairments [11]. Besides these important physiological roles, RIP140 has also recently been shown to regulate key steps during cancer initiation and progression. The aim of this review is to summarize data regarding the role of RIP140 in cancer biology focusing on different solid tumors including ovarian, breast and colon cancers.
Section snippets
Estrogen signaling
Estrogens, including the endogenous ovarian hormone estradiol (E2), play an essential role in the growth, differentiation and homeostasis of a number of target tissues [12], [13]. The biological effects of E2 are mediated through estrogen receptors (ERs) which belong to the nuclear receptor superfamily of ligand-inducible transcription factors [14]. There are two ERs, namely ERα and ERβ, which exhibit specificities in term of ligands, expression and biological activities. The well-known
RIP140 and mammary gland development
By using loss and gain of function mouse models, Nautiyal et al. have recently demonstrated that RIP140 is an essential factor for normal mammary gland development [24]. Mice lacking NRIP1 expression exhibited minimal ductal elongation with no side-branching, whereas RIP140-overexpressing mice (in which human RIP140 expression is driven by the synthetic CAG promoter containing the chicken β-actin promoter and a CMV enhancer [25]) showed increased cell proliferation and ductal branching with
The Wnt signaling pathway in colon cancer
The canonical Wnt/ß-catenin signaling pathway is broadly admitted as essential for gut homeostasis and especially for self-renewal of intestinal stem cells. An essential cytoplasmic signal transducer of this canonical Wnt pathway is β-catenin. In the absence of pathway stimulation by Wnt ligands, β-catenin is phosphorylated and targeted for degradation by the proteasome. The degradation complex responsible for β-catenin destabilization contains the tumor suppressor gene products axin and
RIP140 in hepatocellular carcinomas
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and ranks amongst the most deadly cancers worldwide. It is associated with specific risk factors, including hepatitis infection or high alcohol intake and characterized by phenotypic and molecular heterogeneity. The treatments involve surgical resection or liver transplantation associated with a limited number of systemic therapies, sorafenib currently being the only approved targeted therapy. The Wnt/β-catenin pathway
Future directions
Breast, ovarian and colon cancers are amongst the most frequent or aggressive tumors with major societal impacts. It is therefore important to further decipher the molecular mechanisms involved in the initiation and development of these pathologies in order to improve patient monitoring and care. Gene expression is highly and frequently distorted in malignancy, by both loss and gain of function of transcription factors encoded by oncogenes or tumor suppressor genes. This deregulation of gene
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Acknowledgments
We thank all the members of the Hormone Signaling and Cancer laboratory for their help, discussions and critical reading of the original manuscript. We also thank all the people who shared materials and reagents used in these studies. We are deeply grateful to Beatrice Orsetti who performed the gene copy number analysis. The work was supported by INSERM, the Université de Montpellier, Fondation Lejeune, INCa (2011-054), SIRIC Montpellier and the Institut régional du Cancer de Montpellier (ICM).
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