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1.
Nucleic Acids Res ; 52(7): 3971-3988, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38300787

RESUMEN

The RAVER1 protein serves as a co-factor in guiding the polypyrimidine tract-binding protein (PTBP)-dependent control of alternative splicing (AS). Whether RAVER1 solely acts in concert with PTBPs and how it affects cancer cell fate remained elusive. Here, we provide the first comprehensive investigation of RAVER1-controlled AS in cancer cell models. This reveals a pro-oncogenic role of RAVER1 in modulating tumor growth and epithelial-mesenchymal-transition (EMT). Splicing analyses and protein-association studies indicate that RAVER1 guides AS in association with other splicing regulators, including PTBPs and SRSFs. In cancer cells, one major function of RAVER1 is the stimulation of proliferation and restriction of apoptosis. This involves the modulation of AS events within the miR/RISC pathway. Disturbance of RAVER1 impairs miR/RISC activity resulting in severely deregulated gene expression, which promotes lethal TGFB-driven EMT. Among others, RAVER1-modulated splicing events affect the insertion of protein interaction modules in factors guiding miR/RISC-dependent gene silencing. Most prominently, in all three human TNRC6 proteins, RAVER1 controls AS of GW-enriched motifs, which are essential for AGO2-binding and the formation of active miR/RISC complexes. We propose, that RAVER1 is a key modulator of AS events in the miR/RISC pathway ensuring proper abundance and composition of miR/RISC effectors. This ensures balanced expression of TGFB signaling effectors and limits TGFB induced lethal EMT.


Asunto(s)
Empalme Alternativo , Transición Epitelial-Mesenquimal , MicroARNs , Transición Epitelial-Mesenquimal/genética , Humanos , MicroARNs/metabolismo , MicroARNs/genética , Línea Celular Tumoral , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Proteína de Unión al Tracto de Polipirimidina/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Factores de Empalme Serina-Arginina/metabolismo , Factores de Empalme Serina-Arginina/genética , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/genética , Apoptosis/genética , Factor de Crecimiento Transformador beta/metabolismo , Animales
2.
Biomol NMR Assign ; 16(2): 237-246, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35474152

RESUMEN

The dysbindin domain-containing protein 1 (DBNDD1) is a conserved protein among higher eukaryotes whose structure and function are poorly investigated so far. Here, we present the backbone and side chain nuclear magnetic resonance assignments for the human DBNDD1 protein. Our chemical-shift based secondary structure analysis reveals the human DBNDD1 as an intrinsically disordered protein.


Asunto(s)
Proteínas Intrínsecamente Desordenadas , Disbindina , Humanos , Proteínas Intrínsecamente Desordenadas/química , Espectroscopía de Resonancia Magnética , Resonancia Magnética Nuclear Biomolecular , Estructura Secundaria de Proteína
3.
Biomol NMR Assign ; 15(2): 441-448, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34415548

RESUMEN

Even though the human genome project showed that our DNA contains a mere 20,000 to 25,000 protein coding genes, an unexpectedly large number of these proteins remain functionally uncharacterized. A structural characterization of these "unknown" proteins may help to identify possible cellular tasks. We therefore used a combination of bioinformatics and nuclear magnetic resonance spectroscopy to structurally de-orphanize one of these gene products, the 108 amino acid human uncharacterized protein CXorf51A. Both our bioinformatics analysis as well as the [Formula: see text]H, [Formula: see text]C, [Formula: see text]N backbone and near-complete side-chain chemical shift assignments indicate that it is an intrinsically disordered protein.


Asunto(s)
Proteínas Intrínsecamente Desordenadas
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