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 Table of Contents  
Year : 2015  |  Volume : 1  |  Issue : 1  |  Page : 21-25

Split End Family RNA Binding Proteins: Novel Tumor Suppressors Coupling Transcriptional Regulation with RNA Processing

1 Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, The University of Alabama at Birmingham, Birmingham, AL, USA
2 Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China

Date of Submission11-Jan-2015
Date of Acceptance01-Feb-2015
Date of Web Publication16-Feb-2015

Correspondence Address:
Dr. Xinyang Zhao
1825 University Boulevard, SHEL 703, Birmingham, AL 35294
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Source of Support: None, Conflict of Interest: None

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Split End (SPEN) family proteins have three members: SPEN, RBM15, and RBM15B. SPEN family proteins contain three conserved RNA recognition motifs on the N-terminal region and an SPOC domain on the C-terminal region. RBM15 is fused to MKL1 in chromosome translocation t (1;22), which causes childhood acute megakaryoblastic leukemia (AMKL). Haploinsufficiency of RBM15 in AMKL indicates that RBM15 is a tumor suppressor. Both SPEN and RBM15 are mutated in a variety of cancer types, implying that they are tumor suppressors. SPEN and RBM15are required for the development of multiple organs including hematopoiesis partly via regulating the NOTCH signaling pathway, as well as the WNT signaling pathway in species ranging from Drosophila to mammals. Besides transcriptional regulation, RBM15 regulates RNA export and RNA splicing. In this review, we summarized data in the literature on how the members in SPEN family regulate gene expression at transcription and RNA processing steps. The crosstalk between epigenetic regulation and RNA metabolism is increasingly appreciated in understanding tumorigenesis. Studying the SPEN family of RNA binding proteins will create new perspectives for cancer therapy.

Keywords: RNA processing, Split End, tumor suppressors

How to cite this article:
Su H, Liu Y, Zhao X. Split End Family RNA Binding Proteins: Novel Tumor Suppressors Coupling Transcriptional Regulation with RNA Processing. Cancer Transl Med 2015;1:21-5

How to cite this URL:
Su H, Liu Y, Zhao X. Split End Family RNA Binding Proteins: Novel Tumor Suppressors Coupling Transcriptional Regulation with RNA Processing. Cancer Transl Med [serial online] 2015 [cited 2020 Aug 5];1:21-5. Available from: http://www.cancertm.com/text.asp?2015/1/1/21/151483

  Introduction Top

In 2001, two groups independently discovered a new chromosome translocation in acute megakaryoblastic leukemia (AMKL) from non-Down's syndrome leukemia patients. [1],[2] The t (1;22) translocation yields a fusion protein which consists of an almost full length RBM15 protein fused to MKL1, and both RBM15 and MKL1 are critical for megakaryocytic differentiation [Figure 1]. [3],[4],[5] Therefore, the translocation results in haploinsufficiency of both genes and gain-of-function effect from the fusion product, which interferes functions of RBM15 and MKL1. The fusion protein is proved to be responsible for AMKL development as shown in the RBM15-MKL1 knock-in mouse model. [6] Apart from chromosome translocation, more mutations in members of the Split End (SPEN) family have been found associated with cancer. Analysis of patient samples shows that 11% of adenoid cystic carcinomas contain mutations in SPEN. [7] RBM15 is upregulated in cancer stem cell-like side populations in esophageal carcinoma cell lines. [8] Data from cBioportal indicates that SPEN and RBM15 are mutated and/or amplified in many different kinds of cancers, especially in bladder cancers [Figure 2]. [9] Given that SPEN proteins are often mutated and lose their normal function in cancer, we characterize them as potential tumor suppressors. Nevertheless, more researches are needed to firmly establish the molecular and biological roles of SPEN proteins during development and tumorigenesis.
Figure 1: Schematic drawing of RBM15, MKL1 and the translocation fusion (OTT-MAL) made from the translocation. The domains are marked. RRM: RNA recognition motif; NLS: Nuclear localization signal; MKL: Megakaryoblastic leukemia

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Figure 2: Dysregulation of RBM15 including mutations, deletions, amplification and multiple alternations is found in cancer cell lines derived from different kinds of cancer cells.[12],[13]

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  Molecular Functions of Split End Family RNA Binding Proteins at Transcriptional Regulation and RNA Metabolism Top

RBM15 belongs to the SPEN family which has three major family members: SPEN (SHARP/MINT), RBM15 (OTT1) and OTT3 (RBM15B). They contain three RNA recognition motifs (RRMs) on the N-terminal region and a SPEN-Paralog-Ortholog-Conserved (SPOC) domain on the C-terminal region. All three genes are ubiquitously expressed in all tissues. The functions of these genes are nonredundant, given that individual gene knockouts in mice are lethal.

Studies on the RRMs in SHARP show that multiple RRMs cooperate to achieve specific binding onto the SRA RNA, which is the noncoding RNA and serving as a steroid receptor coactivator. [10],[11] All the RRM domains share similar tertiary structures, and the specificities are determined by the sequences flanking these RRMs. The stem loop structure of SRA RNA is specifically recognized by SHARP RRMs. A specific RNA export element in mouse LTR-retrotransposon is recognized by the RRMs of RBM15, [14] but not the constitutive transport element in the RNA genome of Type D retroviruses. Given that the sequences of SRA RNA and LTR-retrotransposon RNA are different, RBM15 may recognize RNA molecules based on their tertiary structures. It could be a difficult task to find a consensus linear RNA sequence for RBM15 binding. In SHARP's case, specific SRA/SHARP interaction is required for recruitment of SHARP to promoters. Then via its SPOC domain, SHARP further recruits HDAC1 and HDAC2 in the NuRD complex for transcriptional repression. [11] In MCF-7 cells, SHARP attenuates estrogen receptor mediated transcriptional activation through negative feedbacks, as the expression of SHARP is induced by estrogen. Since breast cancer cells proliferate unrestrainedly with the estrogen stimulation, the role of SHARP as a cancer suppressor during tumorigenesis is crucial and needs more study using patient samples and animal models. SHARP also binds to transcriptional coactivator RBP-Jκ/CBF-1 in NOTCH pathway; [15] however, the RRMs of SHARP are not involved in this interaction, while the RRMs in RBM15 as well as RBM15-MKL1 fusion protein are capable of interacting with RBP-Jκ protein to repress NOTCH signaling pathway. [3],[6] Nevertheless, whether RNA molecules are involved in bridging the interaction between RBP-J and the RRMs of RBM15 has not been systematically investigated.

The SPOC domain is a conserved domain found in the SPEN family as well as in proteins such as DIDO1 and PHF3 from other protein families. The crystal structure of the SHARP SPOC domain has already been resolved. [16] SPOC domain directly interacts with the C-terminal region of SMRT/N-CoR complex, and further analysis shows that the phosphorylation on the C-terminal region of SMRT by casein kinase 2 enhances the binding between SMRT complex and SPOC domain. [17] SPOC domain of RBM15 has been shown to be required for the binding toMLL complex, which mediates the trimethylation of H3K4. [18] Although the RBM15 and SHARP share a high degree of homology in their SPOC domains, whether the SPOC domain of RBM15 can directly recruit SMRT complex remains unknown. We think RBM15 SPOC domain might evolve to lose the surface for interaction with SMRT.

Due to RNA binding capability, SPEN proteins are involved in RNA export and processing. Previous studies demonstrated that RBM15 and RBM15B/OTT3 facilitate RNA export by binding to NXF1 and DBP5. [14],[19],[20] RBM15 also retains Herpes viral mRNA by hyper-polyadenylation in nucleus. [21] RBM15 resides in nuclear splicing speckles along with several known splicing proteins including WTAP1. [21] Currently, there is limited biochemical evidence to show that RBM15 is directly involved in RNA splicing. Recent studies in Dr. Glen Raffel's lab demonstrate that H3K4 trimethylation on the c-MPL (thrombopoietin receptor) promoter is positively regulated by RBM15, [23] but how RBM15 regulates alternative RNA splicing of genes in a transcription-coupled manner in hematopoietic stem cells (HSCs) is still under investigation. These data are consistent with the finding that RBM15 interacts with the MLL complex. [16] RBM15 knockdown promotes the production of an exon9 and 10-missing variant of c-MPL mRNA, which produces a truncated c-MPL with no intracellular domain. c-MPL is required for HSC self-renewal apart from its roles in megakaryocytic differentiation. [24] Given that the transgenic mice expressing only the full-length c-MPL produces an excessive amount of platelets, isoforms of c-MPL produced by RBM15-mediated alternative splicing fine-tune the platelet production. [25] Therefore, alternative splicing of c-MPL mRNA regulated by RBM15 fine-tunes the magnitude of megakaryocytic differentiation. RNA immunoprecipitation experiments with anti-RBM15 antibody show that RBM15 binds to 3'UTR regions as well as intron regions of pre-mRNA of over a thousand genes, indicating that transcription-coupled RNA splicing mediated by RBM15 might be a common mechanism. Given that the human SHARP/SPEN protein is involved in transcriptional repression, whether SHARP interacts with the MLL complex via the SPOC domain is still unknown. Other than in human, it has been reported that H3K4 trimethylation in Drosophila cells is also reduced upon SPEN knockout. [26] It is possible that posttranslational modifications on the SPOC domain determine the context-dependent recruitment.

Intriguingly, FPA (the plant ortholog of human RBM15 in Arabidopsis) also regulates histone methylation via RNA processing. FPA facilitates to establish H3K4Me3 on the FLC locus, which encodes a transcriptional repressor that controls the timing of flowering, by mediating the alternative polyadenylation of this gene's antisense RNA. [27],[28],[29] Sonmez et al.[27] used whole genome tiling arrays to demonstrate that FPA not only affects alternative polyadenylation and alternative splicing of many genes, but also regulates DNA methylation profiles.

  Biological Functions of the Split End Family RNA Binding Proteins Top

Besides shared conservative domains, there is little sequence similarity among the SPEN family members. Therefore, it is not surprising that the functions of these family members are usually nonredundant. The MINT (SPEN/SHARP) knockout mice die on embryonic day E12.5-14.5 with multiple organ failures: liver, heart and pancreas and RBM15 knockout mice die on day E9.5. [30],[31],[32] In Drosophila, SHARP (ortholog of human SPEN) and SPENITO (ortholog of human RBM15) functionally antagonize each other during eye development; [33] on the other hand, SHARP and SPENITO have overlapping functions in promoting WNT signaling pathway. [34]

MINT has been proven crucial for the development of multiple organs. MINT -/- mice are embryonic lethal, due to defects in formation of the cardiac septum and muscle. [30] Compared to wild-type counterpart, MINT-null fetal liver cells from E12.5 embryo developed more efficiently into marginal zone B cells after being transferred to recipient mice, also generated a smaller follicular B cell population with no differences in B-1/B-2 cells. [30] Later experiments from Dr. Honjo's group found that MINT knockout fetal liver cells are also defective in T cell development. [35] Yet there is no report on tissue-specific conditional MINT knockout mice. Similar to MINT, RBM15 is also essential for the embryonic development of mice. RBM15 straight knockout is embryonic lethal. Conditional knockout mice (RBM15flox with Sox 2-Cre) show severe defects in trophoblastic and placental development, also often with hyposplenia and cardiac malformations. [31] Given that both MINT and RBM15 regulate a wide range of target genes in signaling and metabolic pathways, [26] these conditional knockout mice could be great disease models for studying cancer or cardiac and metabolic diseases.

In addition to being implicated in embryonic development, RBM15 has also been reported to be important for leukemogenesis. Studying of conditional RBM15 knockout mice (Mx1-Cre) revealed that RBM15 is required for the self-renewal of HSCs, as well as for megakaryocytic differentiation. [32],[36],[37] RBM15 deficiency causes dysregulation of surface receptor expression such as N-cadherin and β-integrin, which leads to miscommunication between bone niche and HSCs. Detailed analysis of RBM15 conditional knockout mice indicates that RBM15 triggers upregulation of c-Myc pathway in hematopoietic cells. Furthermore, low expression of RBM15 leads to decreased production of polyploid megakaryocytes, which mimics the phenotype of c-Myc-overexpressed cells. [37] Apart from gene expression control, RBM15 activity is associated with cellular metabolic status. Microarray analysis of RBM15 target genes in Lin - Sca + Kit + hematopoietic stem/progenitor cells from RBM15 -/- vs. wild type mice indicates that RBM15 regulates metabolism with increased production of respiratory oxidative species. Furthermore, long-term HSCs with RBM15 knockout contain higher mitochondria mass and have a reduction of G0 phase fraction, which is associated with stem cell self-renewal. [36] RBM15 knockout activates p38-mediated stress response in stem cells and activation of p38 pathway has been shown to stimulate differentiation of HSCs. [38] As aforementioned, RBM15 has activity in regulating several RNA processing steps: polyadenylation, splicing, and export. This may in turn affect chromatin modification status such as H3K4 trimethylation as shown in plants. Taken together, RBM15 is a critical coordinator of the metabolic pathway and epigenetic changes. Given that cancer takes a long time to evolve, dysregulations of RBM15-mediated pathways might set a predisposition for cancer development.

Functional disruption of RBM15 is correlated with cancer. RBM15-MKL1 is a causal factor for pediatric AMKL. Mercer et al.[6] demonstrated that transgenic mice with expression of RBM15-Mkl1 from endogenous RBM15 promoter develop low penetrance leukemia with megakaryocytic abnormalities that mimic AMKL features in human patients, such as extramedullary hematopoiesis in spleen and liver. RBM15-Mkl1 initiated leukemia is transplantable, indicating that RBM15-Mkl1 expression induces the generation of leukemic stem cells. Introducing tyrosine kinase mutation c-MPL W515L into RBM15-Mkl1 expressing bone marrow cells produces frank leukemia with shorter latency and severe myelofibrosis, while the transduction of Jak2 V617F mutation cannot cooperate with RBM15-Mkl1 to cause leukemia in bone marrow transplantation models. Gene expression analysis showed that RBM15-Mkl1 disrupts NOTCH pathway by binding to RBP-Jκ and induces RBPJ-mediated transcriptional activation. Further investigation is needed to understand the detailed molecular mechanisms behind this disease.

In summary, the available data emphasize that the SPEN family plays important role in regulating known signaling pathways in cancer development such as NOTCH and WNT pathways, as well as in regulating metabolic status, which is increasingly appreciated in cancer biology. At molecular levels, how the SPEN family couples epigenetic changes with RNA processing remains elusive. Nevertheless, understanding the functions of the SPEN family proteins will give us new insights for finding curative cancer therapy.

  References Top

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