SRSF1 and SRSF9 RNA binding proteins promote Wnt signalling‐mediated tumorigenesis by enhancing β‐catenin biosynthesis

Fu, Yu; Huang, Biao; Shi, Zhen; Han, Jikhyon; Wang, Ying; Huangfu, Jieqiong; Wu, Wei

doi:10.1002/emmm.201202218

Cited by 104 publications

(117 citation statements)

References 80 publications

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“…Although the mechanisms of β-catenin protein degradation are well-described, comparatively little is known about the regulation of its production 24 . Consistent with our findings, others have shown that RBPs can modulate CTNNB1 mRNA metabolism and β-catenin protein expression 25 - 29 . Although a previously published study did not identify a decrease in β-catenin protein expression in hnRNPA2-depleted cells, 7 this may be due to functional redundancy as exemplified by complex mRNA transcript cross- and auto-regulation by hnRNP paralogs 14 , 30 .…”

Section: Discussionsupporting

confidence: 87%

The RNA-binding protein hnRNPA2 regulates β-catenin protein expression and is overexpressed in prostate cancer

et al. 2014

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Introduction The RNA-binding protein hnRNPA2 (HNRNPA2B1) is upregulated in cancer, where it controls alternative pre-mRNA splicing of cancer-relevant genes. Cytoplasmic hnRNPA2 is reported in aggressive cancers, but is functionally uncharacterized. We explored the role of hnRNPA2 in prostate cancer (PCa). Methods: hnRNPA2 function/localization/expression in PCa was determined using biochemical approaches (colony forming/proliferation/luciferase reporter assays/flow cytometry/immunohistocytochemistry). Binding of hnRNPA2 within cancer-relevant 3′-UTR mRNAs was identified by bioinformatics. Results: RNAi-mediated knockdown of hnRNPA2 reduced colony forming and proliferation, while hnRNPA2 overexpression increased proliferation of PCa cells. Nuclear hnRNPA2 is overexpressed in high-grade clinical PCa, and is also observed in the cytoplasm in some cases. Ectopic expression of a predominantly cytoplasmic variant hnRNPA2-ΔRGG also increased PCa cell proliferation, suggesting that cytoplasmic hnRNPA2 may also be functionally relevant in PCa. Consistent with its known cytoplasmic roles, hnRNPA2 was associated with 3′-UTR mRNAs of several cancer-relevant mRNAs including β-catenin (CTNNB1). Both wild-type hnRNPA2 and hnRNPA2-ΔRGG act on CTNNB1 3′-UTR mRNA, increasing endogenous CTNNB1 mRNA expression and β-catenin protein expression and nuclear localization. Conclusion: Nuclear and cytoplasmic hnRNPA2 are present in PCa and appear to be functionally important. Cytoplasmic hnRNPA2 may affect the cancer cell phenotype through 3′-UTR mRNA-mediated regulation of β-catenin expression and other cancer-relevant genes.

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Section: Discussionsupporting

confidence: 87%

The RNA-binding protein hnRNPA2 regulates β-catenin protein expression and is overexpressed in prostate cancer

et al. 2014

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“…The synthesis of ␤-catenin is controlled by two splicing factors, SRSF1 and 9, exhibiting an aging-related decrease [296] that could explain the Wnt/␤-catenin signaling defect. The same two SRSF are overexpressed in cancer cells and promote Wnt-signaling tumorigenesis through the production of ␤-catenin mRNA [367].…”

Section: Adult Stem Cell Exhaustion Related To Defects In Signaling Pmentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.

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“…Moreover, SRSF1, -3, and -9 are overexpressed in a number of cancers and possess oncogenic properties (22,26,31). Previously, we reported increased levels of the three smallest SR proteins, SRSFs 1 to 3, in our W12 model of cervical tumor progression and in patient samples (24).…”

Section: Discussionmentioning

confidence: 61%

“…Unsurprisingly, due to their diverse functions, many SR proteins are overexpressed in a range of tumors (21)(22)(23)(24)(25). Importantly, SRSF1 (ASF/SF2), SRSF3 (SRp20), and SRSF9 (SRp30c) have been shown to possess oncogenic properties (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Increased SRSF levels can result in the production of alternatively spliced RNA isoforms encoding key antiapoptotic, cell proliferation, and epithelial-mesenchymal transition (EMT)-inducing proteins (18).…”

mentioning

confidence: 99%

Human Papillomavirus 16 Oncoprotein Expression Is Controlled by the Cellular Splicing Factor SRSF2 (SC35)

McFarlane

MacDonald

Stevenson

et al. 2015

J Virol

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High-risk human papillomaviruses (HR-HPV) cause anogenital cancers, including cervical cancer, and head and neck cancers. Human papillomavirus 16 (HPV16) is the most prevalent HR-HPV. HPV oncogenesis is driven by two viral oncoproteins, E6 and E7, which are expressed through alternative splicing of a polycistronic RNA to yield four major splice isoforms (E6 full length, E6*I, E6*II, E6*X). The production of multiple mRNA isoforms from a single gene is controlled by serine/arginine-rich splicing factors (SRSFs), and HPV16 infection induces overexpression of a subset of these, SRSFs 1, 2, and 3. In this study, we examined whether these proteins could control HPV16 oncoprotein expression. Small interfering RNA (siRNA) depletion experiments revealed that SRSF1 did not affect oncoprotein RNA levels. While SRSF3 knockdown caused some reduction in E6E7 expression, depletion of SRSF2 resulted in a significant loss of E6E7 RNAs, resulting in reduced levels of the E6-regulated p53 proteins and E7 oncoprotein itself. SRSF2 contributed to the tumor phenotype of HPV16-positive cervical cancer cells, as its depletion resulted in decreased cell proliferation, reduced colony formation, and increased apoptosis. SRSF2 did not affect transcription from the P 97 promoter that controls viral oncoprotein expression. Rather, RNA decay experiments showed that SRSF2 is required to maintain stability of E6E7 mRNAs. These data show that SRSF2 is a key regulator of HPV16 oncoprotein expression and cervical tumor maintenance. H uman papillomaviruses (HPV) infect mucosal and cutaneous epithelia. At least 13 so-called "high-risk" HPV (HR-HPV) infect the anogenital epithelium and can cause persistent lesions that may progress to cancer (1). For example, around 500,000 women worldwide experience anogenital HPV infection, and nearly 300,000 die per annum from cervical cancer. Increasingly, HPV infection is also being linked to oropharyngeal cancer, whereby incidence of this disease is increasing rapidly (2). HPV16 is the most prevalent HR-HPV. HPV-associated tumorigenesis is driven by increased expression of the HPV E6 and E7 oncoproteins (3). E6 promotes ubiquitin-mediated degradation of p53 to inhibit apoptosis, modulates transcription of cell cycle-related genes, induces telomerase activity, controls cell shape and polarity, and activates cap-dependent translation (4). E7 binds and degrades Rb to promote S phase entry and cell division, controls transcription of cell cycle-related genes, and acts as a mitotic mutator (4). IMPORTANCE Expression of the HPV16 oncoproteins E7 and E6 drives HPV-associated tumor formation. Although increased transcription may yield increased levels of E6E7 mRNAs, it is known that theHPV E6 and E7 oncoproteins are expressed from a polycistronic transcript that for HPV16 can potentially produce four different alternatively spliced mRNAs (E6 full length [E6fl], E6*I, E6*II, and E6*X [also called E6*III]) (5, 6). The putative E6* proteins all share the first 44 amino acids of full-length E6 with C-terminal trun...

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SRSF1 and SRSF9 RNA binding proteins promote Wnt signalling‐mediated tumorigenesis by enhancing β‐catenin biosynthesis

Cited by 104 publications

References 80 publications

The RNA-binding protein hnRNPA2 regulates β-catenin protein expression and is overexpressed in prostate cancer

The RNA-binding protein hnRNPA2 regulates β-catenin protein expression and is overexpressed in prostate cancer

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Human Papillomavirus 16 Oncoprotein Expression Is Controlled by the Cellular Splicing Factor SRSF2 (SC35)

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