IMP3 RNP Safe Houses Prevent miRNA-Directed HMGA2 mRNA Decay in Cancer and Development

Jønson, Lars; Christiansen, Jan; Hansen, Thomas V.O.; Vikeså, Jonas; Yamamoto, Yohei; Nielsen, Finn Cilius

doi:10.1016/j.celrep.2014.03.015

Cited by 83 publications

(115 citation statements)

References 67 publications

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“…Our primary approach is not well suited to identify such interactions, as the maximum fragment size we examined was 400 nt. It is clear that long-range interactions do occur; indeed IGF2BP3 control of the HMGA2 transcript is one such example (Jønson et al 2014), as is our discovery of distal control of AREs within the Hmga2 3 ′ UTR. Systematic identification of such interactions requires both knowledge of the regulatory impact of discrete pieces of a 3 ′ UTR, together with experiments that investigate the roles of identified elements within the complete native 3 ′ UTR.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, knockdown of HuR may yield interpretable results when focusing on isolated, discrete 3 ′ -UTR fragments that contain only AREs with high affinity to HuR, but results may not be so clear for a 3 ′ -UTR sequence containing multiple AREs, some of which can bind other ARE-BPs. A recent study identified another RBP that has an important role in HMGA2 regulation: Jønson et al (2014) demonstrated that IGF2BP3 protects let-7 targeted transcripts, and HMGA2 in particular, from miRNA repression by sequestration into "IGF2BP3 granules." Unfortunately, we were unable to address this aspect of Hmga2 biology, as in our hands, shRNA-mediated inhibition of IGF2BP3 had no effect on full-length Hmga2 3 ′ -UTR reporters (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Loss of post-transcriptional regulation, and specifically loss of let-7 targeting (Lee and Dutta 2007;Mayr et al 2007), leads to overexpression of Hmga2 and oncogenic transformation. Interestingly, the RNA binding protein IGF2BP3 has recently been shown to protect the Hmga2 transcript from let-7-mediated repression in embryonic tissues and cancer cells (Jønson et al 2014). While let-7 repression and IGF2BP3 sequestration are clearly important, these alone do not explain the extensive conservation of the Hmga2 3 ′ UTR.…”

Section: Introductionmentioning

confidence: 97%

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Systematic analysis of the Hmga2 3′ UTR identifies many independent regulatory sequences and a novel interaction between distal sites

Kristjánsdóttir

Fogarty

Grimson

2015

RNA

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The 3 ′ untranslated regions (3 ′ UTRs) of mRNAs regulate transcripts by serving as binding sites for regulatory factors, including microRNAs and RNA binding proteins. Binding of such trans-acting factors can control the rates of mRNA translation, decay, and other aspects of mRNA biology. To better understand the role of 3 ′ UTRs in gene regulation, we performed a detailed analysis of a model mammalian 3′ UTR, that of Hmga2, with the principal goals of identifying the complete set of regulatory elements within a single 3 ′ UTR, and determining the extent to which elements interact with and affect one another. Hmga2 is an oncogene whose overexpression in cancers often stems from mutations that remove 3 ′ -UTR regulatory sequences. We used reporter assays in cultured cells to generate maps of cis-regulatory information across the Hmga2 3 ′ UTR at different resolutions, ranging from 50 to 400 nt. We found many previously unidentified regulatory sites, a large number of which were up-regulating. Importantly, the overall location and impact of regulatory sites was conserved between different species (mouse, human, and chicken). By systematically comparing the regulatory impact of 3 ′ -UTR segments of different sizes we were able to determine that the majority of regulatory sequences function independently; only a very small number of segments showed evidence of any interactions. However, we discovered a novel interaction whereby terminal 3 ′ -UTR sequences induced internal up-regulating elements to convert to repressive elements. By fully characterizing one 3 ′ UTR, we hope to better understand the principles of 3 ′ -UTR-mediated gene regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Systematic analysis of the Hmga2 3′ UTR identifies many independent regulatory sequences and a novel interaction between distal sites

Kristjánsdóttir

Fogarty

Grimson

2015

RNA

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“…IGF2BP3 can cause remodeling of the exocrine pancreas when specifically overexpressed in that tissue and is highly expressed in cancer stem cells/tumor-initiating cells in hepatocellular carcinoma (40,41). It has been known that IGF2BP3 targets mRNAs for IGF2, CD44, and the transcription factor HMGA2 (16,42). Further reports on HMGA2 and IGF2BPs have suggested that they may play a role in the self-renewal potential of fetal HSCs (43,44).…”

Section: Cdk6 and Myc Mrnas Are Targets Of Igf2bp3 In Vitro And In Vivomentioning

confidence: 99%

RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation

Palanichamy¹,

Tran²,

Howard³

et al. 2016

Journal of Clinical Investigation

133

193

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Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLLrearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this diseas

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“…2; Jonson et al 2014). These IMP3 mRNP granules have been proposed to function as "cytoplasmic safe houses" for a variety of oncogenes and stemness maintenance genes targeted by miRNAs, particularly let-7 family members.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

et al. 2016

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IMPs, also known as insulin-like growth factor 2 (IGF2) messenger RNA (mRNA)-binding proteins (IGF2BPs), are highly conserved oncofetal RNA-binding proteins (RBPs) that regulate RNA processing at several levels, including localization, translation, and stability. Three mammalian IMP paralogs (IMP1–3) have been identified that are expressed in most organs during embryogenesis, where they are believed to play an important role in cell migration, metabolism, and stem cell renewal. Whereas some IMP2 expression is retained in several adult mouse organs, IMP1 and IMP3 are either absent or expressed at very low levels in most tissues after birth. However, all three paralogs can be re-expressed upon malignant transformation and are found in a broad range of cancer types where their expression often correlates with poor prognosis. IMPs appear to resume their physiological functions in malignant cells, which not only contribute to tumor progression but participate in the establishment and maintenance of tumor cell hierarchies. This review summarizes our current understanding of the functions of IMPs during normal development and focuses on a series of recent observations that have provided new insight into how their physiological functions enable IMPs to play a potentially key role in cancer stem cell maintenance and tumor growth.

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IMP3 RNP Safe Houses Prevent miRNA-Directed HMGA2 mRNA Decay in Cancer and Development

Cited by 83 publications

References 67 publications

Systematic analysis of the Hmga2 3′ UTR identifies many independent regulatory sequences and a novel interaction between distal sites

Systematic analysis of the Hmga2 3′ UTR identifies many independent regulatory sequences and a novel interaction between distal sites

RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation

IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer

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