scholarly journals Prognostic Value of the Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Uveal Melanoma: A Clinico-Pathological and Immunohistochemical Study on a Series of 85 Cases

2021 ◽  
Vol 11 (17) ◽  
pp. 7874
Author(s):  
Giuseppe Broggi ◽  
Luca Falzone ◽  
Matteo Fallico ◽  
Andrea Russo ◽  
Michele Reibaldi ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Rna Binding ◽  
Metastatic Potential ◽  
Splicing Factor ◽  
Survival Times ◽  
Immunohistochemical Expression ◽  
Free Survival ◽  
Metastatic Risk ◽  
Factor Α ◽  
Splicing Factor 1

Uveal melanoma (UM) is the most frequent primary ocular malignancy of adults; it exhibits an almost invariably poor prognosis with onset of liver metastases within 10–15 years after the diagnosis. Serine and arginine-rich splicing factor 1 (SRSF1) is an RNA-binding protein with proto-oncogene functions, including stimulation of angiogenesis, cell migration and cell growth; regarding the complex regulation of tumor angiogenesis, it has been suggested that SRSF1 regulates the alternative splicing of vascular endothelial growth factor-α, promoting the formation of its pro-angiogenic isoform. The immunohistochemical expression of SRSF1 on a series of 85 primary UMs, including 39 metastasizing and 46 non-metastasizing cases, was investigated; to clarify the potential pathogenetic role of SRSF1 in this tumor and its effect on angiogenesis, we correlated our immunohistochemical findings with the clinico-pathological features, the prognostic data and blood vascular microvessel density (MVD) findings of the cases from our series. Cases with higher immunohistochemical expression of SRSF1 also had higher MVD, higher metastatic potential and shorter metastasis-free survival; conversely, cases with lower SRSF1 immunoexpression showed lower MVD, lower metastatic risk and longer metastasis-free survival times. Our results suggested that SRSF1 has a negative prognostic role and a pro-angiogenic function in UM.

scholarly journals Recognition of RNA Branch Point Sequences by the KH Domain of Splicing Factor 1 (Mammalian Branch Point Binding Protein) in a Splicing Factor Complex

2001 ◽  
Vol 21 (15) ◽  
pp. 5232-5241 ◽  
Author(s):  
Hadas Peled-Zehavi ◽  
J. Andrew Berglund ◽  
Michael Rosbash ◽  
Alan D. Frankel
Keyword(s):  
Branch Point ◽  
Fusion Proteins ◽  
Rna Binding ◽  
Binding Protein ◽  
Splicing Factor ◽  
Splice Sites ◽  
Reporter System ◽  
Kh Domain ◽  
Tat Fusion Proteins ◽  
Splicing Factor 1

ABSTRACT Mammalian splicing factor 1 (SF1; also mammalian branch point binding protein [mBBP]; hereafter SF1/mBBP) specifically recognizes the seven-nucleotide branch point sequence (BPS) located at 3′ splice sites and participates in the assembly of early spliceosomal complexes. SF1/mBBP utilizes a “maxi-K homology” (maxi-KH) domain for recognition of the single-stranded BPS and requires a cooperative interaction with splicing factor U2AF65 bound to an adjacent polypyrimidine tract (PPT) for high-affinity binding. To investigate how the KH domain of SF1/mBBP recognizes the BPS in conjunction with U2AF and possibly other proteins, we constructed a transcriptional reporter system utilizing human immunodeficiency virus type 1 Tat fusion proteins and examined the RNA-binding specificity of the complex using KH domain and RNA-binding site mutants. We first established that SF1/mBBP and U2AF cooperatively assemble in our reporter system at RNA sites composed of the BPS, PPT, and AG dinucleotide found at 3′ splice sites, with endogenous proteins assembled along with the Tat fusions. We next found that the activities of the Tat fusion proteins on different BPS variants correlated well with the known splicing efficiencies of the variants, supporting a model in which the SF1/mBBP-BPS interaction helps determine splicing efficiency prior to the U2 snRNP-BPS interaction. Finally, the likely RNA-binding surface of the maxi-KH domain was identified by mutagenesis and appears similar to that used by “simple” KH domains, involving residues from two putative α helices, a highly conserved loop, and parts of a β sheet. Using a homology model constructed from the cocrystal structure of a Nova KH domain-RNA complex (Lewis et al., Cell 100:323–332, 2000), we propose a plausible arrangement for SF1/mBBP-U2AF complexes assembled at 3′ splice sites.

scholarly journals Spliceosome Mutations in Uveal Melanoma

2020 ◽  
Vol 21 (24) ◽  
pp. 9546
Author(s):  
Josephine Q.N. Nguyen ◽  
Wojtek Drabarek ◽  
Serdar Yavuzyigitoglu ◽  
Eva Medico Salsench ◽  
Robert M. Verdijk ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Metastatic Disease ◽  
Late Onset ◽  
Metastatic Potential ◽  
Vital Role ◽  
Tumor Classification ◽  
Splicing Factor ◽  
Driver Genes ◽  
Distinct Subgroup ◽  
Recurrent Mutations

Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies.

scholarly journals Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Study

2021 ◽  
Vol 18 (12) ◽  
pp. 6249
Author(s):  
Giuseppe Broggi ◽  
Giuseppe Angelico ◽  
Veronica Filetti ◽  
Caterina Ledda ◽  
Claudia Lombardo ◽  
...  
Keyword(s):  
Prognostic Biomarker ◽  
Splicing Factor ◽  
Malignant Neoplasms ◽  
Cell Nuclei ◽  
Immunohistochemical Expression ◽  
Preliminary Study ◽  
Splicing Factor 1 ◽  
Oncogenic Function ◽  
Immunohistochemical Analyses

The Serine and Arginine-Rich Splicing Factor 1 (SRSF1) has a proto-oncogenic function, being associated with angiogenesis and frequently overexpressed in many human malignant neoplasms. Its immunohistochemical expression has never been investigated in malignant pleural mesothelioma (MPM). We evaluated SRSF1 immunoexpression and its possible relation to angiogenesis in a selected cohort of 10 fluoro-edenite(FE)-induced MPM cases. Methods: Immunohistochemical analyses with an anti-SRSF1 antibody were performed. We interpreted the cases as positive if tumor cell nuclei were stained; a semi-quantitative analysis of the cases was performed by evaluating the intensity of staining and the percentage of tumor positive cells. A microvessel density (MVD) count was also performed. Results: High and low immunoexpressions of SRSF1 were seen in six and four MPMs, respectively. A trend of shorter overall survival was found in FE-induced MPM patients with SRSF1 overexpression. In addition, a significant association between high-MVD and high SRSF1 immunoexpression (p = 0.0476) was found. Conclusions: SRSF1 appears to be involved in MPM pathogenesis and its immunoexpression may represent a prognostic biomarker capable of identifying subgroups of patients with different prognosis. However, given the preliminary nature of the present study, further investigations on larger series, and additional in vitro studies, are required to validate our findings.

scholarly journals Systematic characterization of branch point binding protein, splicing factor 1, gene family in plant development and stress responses

2019 ◽  
Author(s):  
Kai-Lu Zhang ◽  
Zhen Feng ◽  
Jing-Fang Yang ◽  
Tian Yuan ◽  
Di Zhang ◽  
...  
Keyword(s):  
Gene Family ◽  
Plant Species ◽  
Stress Responses ◽  
Messenger Rna ◽  
Rna Binding ◽  
Binding Protein ◽  
Splicing Factor ◽  
Binding Motif ◽  
Splicing Factor 1

Abstract Background: Among eukaryotic organisms, the splicing of nuclear precursor messenger RNA (pre-mRNA) is a process of introns excision and sequentially joining of exons, leading multi-exonic genes to generate multiple splicing isoforms at transcription level. This process is carried out by a super-protein complex defined as spliceosome. Specifically, splicing factor 1/branchpoint binding protein (SF1/BBP) is a single protein that can bind to the intronic branchpoint sequence (BPS), connecting 5’ and 3’ splice site binding complexes during early spliceosome assembly. The molecular function of this protein has been extensively investigated in yeast, metazoan and mammals. However, their counterparts in plants are seldomly reported. Results: Here, we conducted a systematic characterization of SF1 gene family across plant lineage. In this work, a total of 92 sequences from 59 plant species were identified. Phylogenetic relationships of these sequences were constructed and subsequent bioinformatic analysis suggested that this family is likely originated from an ancient gene transposition duplication event. Most plant species were shown to maintain a single copy of this gene. Furthermore, an additional RNA binding motif (RRM) existed in most members of this gene family in comparison to their animal and yeast counterparts, indicating their potential role conserved in plant lineage. Conclusion: Our comprehensive analysis presents general feature of gene and protein structure of this splicing factor family and will provide fundamental information for further functional studies in plants.

scholarly journals Genomic, Prognostic, and Cell-Signaling Advances in Uveal Melanoma

2013 ◽  
pp. 388-391 ◽  
Author(s):  
J. William Harbour
Keyword(s):  
Uveal Melanoma ◽  
Histone Deacetylase Inhibitors ◽  
Clinical Laboratory ◽  
Germ Line ◽  
Mapk Pathway ◽  
Familial Cancer ◽  
Metastatic Potential ◽  
Cancer Syndrome ◽  
Sequencing Technologies ◽  
Metastatic Risk

Uveal melanoma (UM) is the second-most common form of melanoma and the most common primary intraocular malignancy. Up to one-half of patients are at risk for fatal metastatic disease. The metastatic potential of an individual tumor can be accurately determined by analysis of a fine-needle aspirate with gene expression profiling assay that is available for routine clinical use through a commercial Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The test renders one of two results—class 1 (low metastatic risk) or class 2 (high metastatic risk)—and has been extensively validated in multiple centers. Until recently, the genetic mutations and signaling aberrations in UM were largely unknown. With the advent of new genomic sequencing technologies, however, the molecular landscape of UM is rapidly emerging. Mutations in the Gq alpha subunits GNAQ and GNA11 are mutually exclusive and represent early or initiating events that constitutively activate the MAPK pathway. Mutations in BRCA1-associated protein-1 ( BAP1) and splicing factor 3B subunit 1 ( SF3B1) also appear to be largely mutually exclusive, and they occur later in tumor progression. BAP1 mutations are strongly associated with metastasis, whereas SF3B1 mutations are associated with a more favorable outcome. BAP1 mutations can arise in the germ line, leading to a newly described BAP1 familial cancer syndrome. These discoveries have led to new clinical trials to assess several classes of compounds, including MEK, protein kinase C, and histone deacetylase inhibitors, in the adjuvant setting for high-risk patients identified as class 2, as well as in the setting of advanced disseminated disease.

scholarly journals The Macro-Autophagy-Related Protein Beclin-1 Immunohistochemical Expression Correlates With Tumor Cell Type and Clinical Behavior of Uveal Melanoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Giuseppe Broggi ◽  
Antonio Ieni ◽  
Daniela Russo ◽  
Silvia Varricchio ◽  
Lidia Puzzo ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Human Cancer ◽  
Malignant Neoplasm ◽  
Disease Free Survival ◽  
Beclin 1 ◽  
Survival Times ◽  
Immunohistochemical Expression ◽  
Prognostic Role ◽  
Long Time ◽  
Related Proteins

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10–15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.

scholarly journals Systematic characterization of branch point binding protein, splicing factor 1, gene family in plant development and stress responses

2019 ◽  
Author(s):  
Kai-Lu Zhang ◽  
Zhen Feng ◽  
Jing-Fang Yang ◽  
Tian Yuan ◽  
Di Zhang ◽  
...  
Keyword(s):  
Gene Family ◽  
Plant Species ◽  
Stress Responses ◽  
Messenger Rna ◽  
Rna Binding ◽  
Binding Protein ◽  
Splicing Factor ◽  
Binding Motif ◽  
Splicing Factor 1

Abstract Among eukaryotic organisms, the splicing of nuclear precursor messenger RNA (pre-mRNA) is a process of introns excision and sequentially joining of exons, leading multi-exonic genes to generate multiple splicing isoforms at transcription level. This process is carried out by a super-protein complex defined as spliceosome. Specifically, splicing factor 1/branchpoint binding protein (SF1/BBP) is a single protein that can bind to the intronic branchpoint sequence (BPS), connecting 5’ and 3’ splice site binding complexes during early spliceosome assembly. The molecular function of this protein has been extensively investigated in yeast, metazoan and mammals. However, their counterparts in plants are seldomly reported. To this end, we conducted a systematic characterization of SF1 gene family across plant lineage. In this work, a total of 92 sequences from 59 plant species were identified. Phylogenetic relationships of these sequences were constructed and subsequent bioinformatic analysis suggested that this family is likely originated from an ancient gene transposition duplication event. Most plant species were shown to maintain a single copy of this gene. Furthermore, an additional RNA binding motif (RRM) existed in most members of this gene family in comparison to their animal and yeast counterparts, indicating their potential role conserved in plant lineage. Our analysis presents general feature of gene and protein structure of this splicing factor family and will provide fundamental information for further functional studies in plants.

scholarly journals Diagnostic Utility of the Immunohistochemical Expression of Serin and Arginine Rich Splicing Factor 1 (SRSF1) in the Differential Diagnosis of Adult Gliomas

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2086
Author(s):  
Giuseppe Broggi ◽  
Lucia Salvatorelli ◽  
Davide Barbagallo ◽  
Francesco Certo ◽  
Roberto Altieri ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Giant Cell ◽  
Pleomorphic Xanthoastrocytoma ◽  
Splicing Factor ◽  
Immunohistochemical Expression ◽  
Pilocytic Astrocytomas ◽  
Diagnostic Role ◽  
Splicing Factor 1 ◽  
Giant Cell Astrocytoma

Background: The aim of this study was to investigate the immunohistochemical expression and distribution of serine and arginine rich splicing factor 1 (SRSF1) in a series of 102 cases of both diffuse and circumscribed adult gliomas to establish the potential diagnostic role of this protein in the differential diagnosis of brain tumors. Methods: This retrospective immunohistochemical study included 42 glioblastoma cases, 21 oligodendrogliomas, 15 ependymomas, 15 pilocytic astrocytomas, 5 sub-ependymal giant cell astrocytoma and 4 pleomorphic xanthoastrocytomas. Results: Most glioblastoma (81%), oligodendroglioma (71%), sub-ependymal giant cell astrocytoma (80%) and pleomorphic xanthoastrocytoma (75%) cases showed strong SRSF1 immunoexpression, while no detectable staining was found in the majority of ependymomas (87% of cases) and pilocytic astrocytomas (67% of cases). Conclusions: The immunohistochemical expression of SRSF1 may be a promising diagnostic marker of astrocytomas and oligodendrogliomas and its increased expression might allow for excluding entities that often enter into differential diagnosis, such as ependymomas and pilocytic astrocytomas.

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