Splice variants of RAS—translational significance

Rásó, Erzsébet

doi:10.1007/s10555-020-09920-8

Cited by 13 publications

(10 citation statements)

References 77 publications

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“…At the same time, KRAS4B will only be given the farnesyl radical. 27 , 28 These are critical differences with great importance regarding targeted therapy.…”

Section: Krasmentioning

confidence: 99%

“…Using genetic engineering techniques like CRIPS/Cas and TALEN, 74 the endogenous TCR can be silenced, and then, transduction of a new laboratory-designed TCR construct can be done for another expression on T-cells and induction of a specific response against cells presenting certain HLA-epitope complexes derived from KRAS-mutant variants. 75 …”

Section: Krasmentioning

confidence: 99%

“…In most reports, the most frequent exon 14 alterations were splice donor mutation and PRs to either selective or multi-targeted kinase inhibitors. 108 …”

Section: Metmentioning

confidence: 99%

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KRAS and MET in non-small-cell lung cancer: two of the new kids on the ‘drivers’ block

García-Robledo

Rosell

Ruíz-Patiño

et al. 2022

Ther Adv Respir Dis

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Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced to identify various critical oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalized treatment based on the tumor’s molecular genomics. This review presents a comprehensive review of the biology, new therapeutic interventions, and resistance patterns of two well-defined subgroups, tumors with KRAS and MET alterations. We also discuss the status of molecular testing practices for these two key oncogenic drivers, considering the progressive introduction of next-generation sequencing (NGS) and RNA sequencing in regular clinical practice.

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“…At the same time, KRAS4B will only be given the farnesyl radical. 27 , 28 These are critical differences with great importance regarding targeted therapy.…”

Section: Krasmentioning

confidence: 99%

Section: Krasmentioning

confidence: 99%

See 1 more Smart Citation

KRAS and MET in non-small-cell lung cancer: two of the new kids on the ‘drivers’ block

García-Robledo

Rosell

Ruíz-Patiño

et al. 2022

Ther Adv Respir Dis

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“…Quantification of Ras isoform expression during development by real-time polymerase chain reaction (PCR) in mouse tissues indicated a relative contribution of KRas4B > > NRas ≥ KRas4A > HRas to total Ras expression (Newlaczyl et al 2017 ), where KRas4B is about 60–99% of all Ras transcripts. Recent data have also suggested that spliced variants are translationally significant (Raso 2020 ). This may reflect the dependence of multiple factors, including cell type, tissue heterogeneity, timing, sparsity of data, defining flexible statistical frameworks for complex differential patterns in gene expression, assigning a reference, errors and missing data, and from our standpoint as we discuss here, key factors are measuring chromatin accessibility (Buenrostro et al 2015 ; Cusanovich et al 2015 ) and epigenetics, such as DNA methylation (Karemaker and Vermeulen 2018 ) and more (Lahnemann et al 2020 ).…”

Section: Differential Ras Isoform Expressionmentioning

confidence: 99%

Ras isoform-specific expression, chromatin accessibility, and signaling

et al. 2021

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The anchorage of Ras isoforms in the membrane and their nanocluster formations have been studied extensively, including their detailed interactions, sizes, preferred membrane environments, chemistry, and geometry. However, the staggering challenge of their epigenetics and chromatin accessibility in distinct cell states and types, which we propose is a major factor determining their specific expression, still awaits unraveling. Ras isoforms are distinguished by their C-terminal hypervariable region (HVR) which acts in intracellular transport, regulation, and membrane anchorage. Here, we review some isoform-specific activities at the plasma membrane from a structural dynamic standpoint. Inspired by physics and chemistry, we recognize that understanding functional specificity requires insight into how biomolecules can organize themselves in different cellular environments. Within this framework, we suggest that isoform-specific expression may largely be controlled by the chromatin density and physical compaction, which allow (or curb) access to “chromatinized DNA.” Genes are preferentially expressed in tissues: proteins expressed in pancreatic cells may not be equally expressed in lung cells. It is the rule—not an exception, and it can be at least partly understood in terms of chromatin organization and accessibility state. Genes are expressed when they can be sufficiently exposed to the transcription machinery, and they are less so when they are persistently buried in dense chromatin. Notably, chromatin accessibility can similarly determine expression of drug resistance genes.

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“…Small GTPases contain a diverse set of exons with propensity for alternative splicing that can impact biology, including neurodevelopmental disorders and cancer ( Lee et al, 2022 ). Within cancer, splicing changes in small GTPases have been noted for genes including NRAS , KRAS , HRAS , and RAC1 ( Rásó, 2020 ). The Neuroblastoma RAS ( NRAS ) gene has five expressed isoforms, with two of the isoforms elevated in melanoma patients ( Duggan et al, 2019 ; Yan et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

Das

Sherry

Vaughan

et al. 2022

Front. Cell Dev. Biol.

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The small GTPase family is well-studied in cancer and cellular physiology. With 162 annotated human genes, the family has a broad expression throughout cells of the body. Members of the family have multiple exons that require splicing. Yet, the role of splicing within the family has been underexplored. We have studied the splicing dynamics of small GTPases throughout 41,671 samples by integrating Nanopore and Illumina sequencing techniques. Within this work, we have made several discoveries. 1). Using the GTEx long read data of 92 samples, each small GTPase gene averages two transcripts, with 83 genes (51%) expressing two or more isoforms. 2). Cross-tissue analysis of GTEx from 17,382 samples shows 41 genes (25%) expressing two or more protein-coding isoforms. These include protein-changing transcripts in genes such as RHOA, RAB37, RAB40C, RAB4B, RAB5C, RHOC, RAB1A, RAN, RHEB, RAC1, and KRAS. 3). The isolation and library technique of the RNAseq influences the abundance of non-sense-mediated decay and retained intron transcripts of small GTPases, which are observed more often in genes than appreciated. 4). Analysis of 16,243 samples of “Blood PAXgene” identified seven genes (3.7%; RHOA, RAB40C, RAB4B, RAB37, RAB5B, RAB5C, RHOC) with two or more transcripts expressed as the major isoform (75% of the total gene), suggesting a role of genetics in altering splicing. 5). Rare (ARL6, RAB23, ARL13B, HRAS, NRAS) and common variants (GEM, RHOC, MRAS, RAB5B, RERG, ARL16) can influence splicing and have an impact on phenotypes and diseases. 6). Multiple genes (RAB9A, RAP2C, ARL4A, RAB3A, RAB26, RAB3C, RASL10A, RAB40B, and HRAS) have sex differences in transcript expression. 7). Several exons are included or excluded for small GTPase genes (RASEF, KRAS, RAC1, RHEB, ARL4A, RHOA, RAB30, RHOBTB1, ARL16, RAP1A) in one or more forms of cancer. 8). Ten transcripts are altered in hypoxia (SAR1B, IFT27, ARL14, RAB11A, RAB10, RAB38, RAN, RIT1, RAB9A) with RHOA identified to have a transient 3′UTR RNA base editing at a conserved site found in all of its transcripts. Overall, we show a remarkable and dynamic role of splicing within the small GTPase family that requires future explorations.

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Splice variants of RAS—translational significance

Cited by 13 publications

References 77 publications

KRAS and MET in non-small-cell lung cancer: two of the new kids on the ‘drivers’ block

KRAS and MET in non-small-cell lung cancer: two of the new kids on the ‘drivers’ block

Ras isoform-specific expression, chromatin accessibility, and signaling

The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing

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