scholarly journals Alternative Splicing Programs in Prostate Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Claudio Sette
Keyword(s):  
Prostate Cancer ◽  
Alternative Splicing ◽  
Protein Isoforms ◽  
Splicing Regulation ◽  
Therapeutic Approaches ◽  
Male Population ◽  
Incurable Disease ◽  
Prostate Cells ◽  
Mrna Variants ◽  
Alternatively Spliced

Prostate cancer (PCa) remains one of the most frequent causes of death for cancer in the male population. Although the initial antiandrogenic therapies are efficacious, PCa often evolves into a hormone-resistant, incurable disease. The genetic and phenotypic heterogeneity of this type of cancer renders its diagnosis and cure particularly challenging. Mounting evidence indicates that alternative splicing, the process that allows production of multiple mRNA variants from each gene, contributes to the heterogeneity of the disease. Key genes for the biology of normal and neoplastic prostate cells, such as those encoding for the androgen receptor and cyclin D1, are alternatively spliced to yield protein isoforms with different or even opposing functions. This review illustrates some examples of genes whose alternative splicing regulation is relevant to PCa biology and discusses the possibility to exploit alternative splicing regulation as a novel tool for prognosis, diagnosis, and therapeutic approaches to PCa.

Abstract 2083: Alternative splicing regulation by the androgen receptor in prostate cancer cells

2020 ◽  
Author(s):  
Lucas Germain ◽  
Camille Lafront ◽  
Jolyane Beaudette ◽  
Raghavendra Tejo Karthik Poluri ◽  
Cindy Weidmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Splicing Regulation ◽  
Prostate Cancer Cells

scholarly journals Expression of PSA-RP2, an alternatively spliced variant from the PSA gene, is increased in prostate cancer tissues but the protein is not secreted from prostate cancer cells

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
Astrid K. Whitbread ◽  
Tara L. Veveris-Lowe ◽  
Ying Dong ◽  
Olivia L. Tan ◽  
Robert Gardiner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Seminal Fluid ◽  
Prostate Cancer Cells ◽  
Qrt Pcr ◽  
Prostate Cells ◽  
Alternatively Spliced ◽  
Pc3 Cells ◽  
Variant Transcript ◽  
Cancer Tissues ◽  
Spliced Variant

Abstract PSA-RP2 is a variant transcript expressed from the PSA gene that is conserved in gorillas, chimpanzees and humans suggesting a particular relevance for this transcript in these primates. We demonstrated by qRT-PCR that PSA-RP2 is upregulated in prostate cancer compared with benign prostatic hyperplasia tissues. The PSA-RP2 protein was not detected in seminal fluid and was cytoplasmically localised but not secreted from LNCaP or transfected PC3 prostate cells, despite secretion from transfected Cos-7 and HEK293 kidney cell lines. PSA-RP2-transfected PC3 cells showed slightly decreased proliferation and increased migration towards PC3-conditioned medium that could suggest a functional role in prostate cancer.

scholarly journals Influence of Intron Length on Alternative Splicing of CD44

1998 ◽  
Vol 18 (10) ◽  
pp. 5930-5941 ◽  
Author(s):  
Martyn V. Bell ◽  
Alison E. Cowper ◽  
Marie-Paule Lefranc ◽  
John I. Bell ◽  
Gavin R. Screaton
Keyword(s):  
Alternative Splicing ◽  
Genomic Structure ◽  
Single Gene ◽  
Intron Length ◽  
Protein Isoforms ◽  
Major Influence ◽  
Eukaryotic Genes ◽  
Alternatively Spliced ◽  
Alternatively Spliced Exons

ABSTRACT Although the splicing of transcripts from most eukaryotic genes occurs in a constitutive fashion, some genes can undergo a process of alternative splicing. This is a genetically economical process which allows a single gene to give rise to several protein isoforms by the inclusion or exclusion of sequences into or from the mature mRNA. CD44 provides a unique example; more than 1,000 possible isoforms can be produced by the inclusion or exclusion of a central tandem array of 10 alternatively spliced exons. Certain alternatively spliced exons have been ascribed specific functions; however, independent regulation of the inclusion or skipping of each of these exons would clearly demand an extremely complex regulatory network. Such a network would involve the interaction of many exon-specific trans-acting factors with the pre-mRNA. Therefore, to assess whether the exons are indeed independently regulated, we have examined the alternative exon content of a large number of individual CD44 cDNA isoforms. This analysis shows that the downstream alternatively spliced exons are favored over those lying upstream and that alternative exons are often included in blocks rather than singly. Using a novel in vivo alternative splicing assay, we show that intron length has a major influence upon the alternative splicing of CD44. We propose a kinetic model in which short introns may overcome the poor recognition of alternatively spliced exons. These observations suggest that for CD44, intron length has been exploited in the evolution of the genomic structure to enable tissue-specific patterns of splicing to be maintained.

scholarly journals Alternative REST Splicing Underappreciated

2017 ◽  
Author(s):  
Guo-Lin Chen ◽  
Gregory M. Miller
Keyword(s):  
Alternative Splicing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Protein Isoforms ◽  
Multiple Protein ◽  
Mrna Variants ◽  
Cellular Context ◽  
Active Transcription ◽  
Context Dependent ◽  
Ageing Brain

As a major orchestrator of the cellular epigenome, the repressor element-1 silencing transcription factor (REST) can either repress or activate thousands of genes depending on cellular context, suggesting a highly context-dependent REST function tuned by environmental cues. While REST shows cell-type non-selective active transcription1, an N-terminal REST4 isoform caused by alternative splicing – inclusion of an extra exon (N3c) which introduces a premature stop codon – has been implicated in neurogenesis and tumorigenesis2-5. Recently, in line with established epigenetic regulation of pre-mRNA splicing6,7, we demonstrated that REST undergoes extensive, context-dependent alternative splicing which results in the formation of a large number of mRNA variants predictive of multiple protein isoforms8. Supported by that immunoblotting/-staining with different anti-REST antibodies yield inconsistent results, alternative splicing allows production of various structurally and functionally different REST protein isoforms in response to shifting physiological requirements, providing a reasonable explanation for the diverse, highly context-dependent REST function. However, REST isoforms might be differentially assayed or manipulated, leading to data misinterpretation and controversial findings. For example, in contrast to the proposed neurotoxicity of elevated nuclear REST in ischemia9 and Huntington’s disease10,11, Lu et al. recently reported decreased nuclear REST in Alzheimer’s disease and neuroprotection of REST in ageing brain12. Unfortunately, alternative REST splicing was largely neglected by Lu et al., making it necessary for a reevaluation of their findings.

scholarly journals MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing

2019 ◽  
Author(s):  
Joun Park ◽  
Yi Zhu ◽  
Xianzun Tao ◽  
Jennifer M. Brazill ◽  
Chong Li ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Stress Response ◽  
Stress Resistance ◽  
Stem Loop ◽  
Stress Protection ◽  
Stem Loop Structure ◽  
Nicotinamide Mononucleotide ◽  
Mrna Variants ◽  
Alternatively Spliced ◽  
Essential Enzyme

SUMMARYUnderstanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stem-loop structure. While NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance.

scholarly journals Down but not out? A novel protein isoform of the estrogen receptor alpha is expressed in the estrogen receptor alpha knockout mouse

2002 ◽  
Vol 29 (3) ◽  
pp. 281-286 ◽  
Author(s):  
M Kos ◽  
S Denger ◽  
G Reid ◽  
KS Korach ◽  
F Gannon
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Binding Capacity ◽  
Protein Isoforms ◽  
Uterine Tissue ◽  
Receptor Alpha ◽  
Mrna Variants ◽  
Alternatively Spliced ◽  
Protein Isoform ◽  
And Function

The mouse knockout of the estrogen receptor alpha (ERalpha) gene, known as alphaERKO, has been extensively used for several years to study the role and function of ERalpha. Residual estradiol binding capacity in uterine tissue of 5-10% raised doubts if this knockout is a genuine null mutation of ERalpha. Although alternatively spliced ERalpha mRNA variants in the alphaERKO mouse were reported previously, the corresponding protein isoforms have not been detected to date. Here we show that a variant ERalpha protein, 61 kDa in size, is expressed in the uterine tissue of alphaERKO mice as a result of an alternative splicing. The transactivation capability of this protein is cell dependent and can be as high as 75% of the wild type ERalpha.

scholarly journals Evolutionary conservation of the structure and expression of alternatively spliced Ultrabithorax isoforms from Drosophila.

Genetics ◽  
1994 ◽  
Vol 136 (3) ◽  
pp. 965-977
Author(s):  
H M Bomze ◽  
A J López
Keyword(s):  
Alternative Splicing ◽  
Protein Function ◽  
Developmental Regulation ◽  
Expression Patterns ◽  
Proximal Region ◽  
Amino Acid Sequences ◽  
Drosophila Virilis ◽  
Protein Isoforms ◽  
Developmentally Regulated ◽  
Alternatively Spliced

Abstract In Drosophila melanogaster, alternatively spliced mRNAs from the homeotic gene Ultrabithorax (Ubx) encode a family of structurally distinct homeoprotein isoforms. The developmentally regulated expression patterns of these isoforms suggest that they have specialized stage- and tissue-specific functions. To evaluate the functional importance of UBX isoform diversity and gain clues to the mechanism that regulates processing of Ubx RNAs, we have investigated whether the Ubx RNAs of other insects undergo similar alternative splicing. We have isolated and characterized Ubx cDNA fragments from D. melanogaster, Drosophila pseudoobscura, Drosophila hydei and Drosophila virilis, species separated by as much as 60 million years of evolution, and have found that three aspects of Ubx RNA processing have been conserved. (1) These four species exhibit identical patterns of optional exon use in a region adjacent to the homeodomain. (2) These four species produce the same family of UBX protein isoforms with identical amino acid sequences in the optional exons, even though the common amino-proximal region has undergone substantial divergence. The nucleotide sequences of the optional exons, including third positions of rare codons, have also been conserved strongly, suggesting functional constraints that are not limited to coding potential. (3) The tissue- and stage-specific patterns of expression of different UBX isoforms are identical among these Drosophila species, indicating that the developmental regulation of the alternative splicing events has also been conserved. These findings argue for an important role of alternative splicing in Ubx function. We discuss the implications of these results for models of UBX protein function and the mechanism of alternative splicing.

Alternative splicing regulation by the androgen receptor in prostate cancer cells

2020 ◽  
Vol 202 ◽  
pp. 105710 ◽  
Author(s):  
Lucas Germain ◽  
Camille Lafront ◽  
Jolyane Beaudette ◽  
Raghavendra Tejo Karthik Poluri ◽  
Cindy Weidmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Alternative Splicing ◽  
Cancer Cells ◽  
Splicing Regulation ◽  
Prostate Cancer Cells

scholarly journals RNA Interference Knockdown of hU2AF35 Impairs Cell Cycle Progression and Modulates Alternative Splicing of Cdc25 Transcripts

2006 ◽  
Vol 17 (10) ◽  
pp. 4187-4199 ◽  
Author(s):  
Teresa Raquel Pacheco ◽  
Luís Ferreira Moita ◽  
Anita Quintal Gomes ◽  
Nir Hacohen ◽  
Maria Carmo-Fonseca
Keyword(s):  
Cell Cycle ◽  
Alternative Splicing ◽  
Rna Interference ◽  
Cell Cycle Progression ◽  
Protein Isoforms ◽  
Cell Cycle Gene ◽  
Mitotic Progression ◽  
Cycle Progression ◽  
Specific Subset ◽  
Alternatively Spliced

U2AF is a heterodimeric splicing factor composed of a large (U2AF65) and a small (U2AF35) subunit. In humans, alternative splicing generates two U2AF35 variants, U2AF35a and U2AF35b. Here, we used RNA interference to specifically ablate the expression of each isoform in HeLa cells. Our results show that knockdown of the major U2AF35a isoform reduced cell viability and impaired mitotic progression, leading to accumulation of cells in prometaphase. Microarray analysis revealed that knockdown of U2AF35a affected the expression level of ∼500 mRNAs, from which >90% were underrepresented relative to the control. Among mRNAs underrepresented in U2AF35a-depleted cells we identified an essential cell cycle gene, Cdc27, for which there was an increase in the ratio between unspliced and spliced RNA and a significant reduction in protein level. Furthermore, we show that depletion of either U2AF35a or U2AF35b altered the ratios of alternatively spliced isoforms of Cdc25B and Cdc25C transcripts. Taken together our results demonstrate that U2AF35a is essential for HeLa cell division and suggest a novel role for both U2AF35 protein isoforms as regulators of alternative splicing of a specific subset of genes.

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