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1.
Cell ; 176(5): 1054-1067.e12, 2019 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-30773316

RESUMEN

Vault RNAs (vtRNA) are small non-coding RNAs transcribed by RNA polymerase III found in many eukaryotes. Although they have been linked to drug resistance, apoptosis, and viral replication, their molecular functions remain unclear. Here, we show that vault RNAs directly bind the autophagy receptor sequestosome-1/p62 in human and murine cells. Overexpression of human vtRNA1-1 inhibits, while its antisense LNA-mediated knockdown enhances p62-dependent autophagy. Starvation of cells reduces the steady-state and p62-bound levels of vault RNA1-1 and induces autophagy. Mechanistically, p62 mutants that fail to bind vtRNAs display increased p62 homo-oligomerization and augmented interaction with autophagic effectors. Thus, vtRNA1-1 directly regulates selective autophagy by binding p62 and interference with oligomerization, a critical step of p62 function. Our data uncover a striking example of the potential of RNA to control protein functions directly, as previously recognized for protein-protein interactions and post-translational modifications.


Asunto(s)
Autofagia/genética , Partículas Ribonucleoproteicas en Bóveda/genética , Partículas Ribonucleoproteicas en Bóveda/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Línea Celular , Células HeLa , Humanos , Ratones , Células RAW 264.7 , ARN/metabolismo , ARN no Traducido/metabolismo , ARN no Traducido/fisiología , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo
2.
Biochim Biophys Acta Mol Cell Res ; 1867(12): 118851, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32918981

RESUMEN

Connexins (Cx), the basic subunit of gap junctions, play important roles in cell homeostasis, and their abnormal expression and function are associated with human hereditary diseases and cancers. In tumorigenesis, connexins were observed to have both anti-tumorigenic and pro-tumorigenic roles in a context- and stage-dependent manner. Initially, Cx26 and Cx43 were thought to be the only connexins involved in normal breast homeostasis and breast cancer. Later on, association of Cx32 expression with lymph node metastasis of breast cancer and subsequent demonstration of its expression in normal breast tissue suggested that Cx32 contributes to breast tissue homeostasis. Here, we aimed to determine the effects of Cx32 on normal breast cells, MCF10A, and on breast cancer cells, MDA-MB-231. Cx32 overexpression had profound effects on MCF10A cells, decreasing cell proliferation by increasing the doubling time of MCF10A. Furthermore, MCF10A cells acquired mesenchymal-like appearance upon Cx32 expression and had increased migration capacity and expression of both E-cadherin and vimentin. In contrast, Cx32 overexpression altered the EMT markers of MDA-MB-231 by increasing the expression of mesenchymal markers, such as slug and vimentin, and decreasing E-cadherin expression without affecting their proliferation and morphology. Our results indicate, for the first time in the literature, that Cx32 has tumor-promoting roles in MCF10A and MDA-MB-231 cells.


Asunto(s)
Neoplasias de la Mama/genética , Proliferación Celular/genética , Conexinas/genética , Metástasis Linfática/genética , Neoplasias de la Mama/patología , Comunicación Celular/genética , Línea Celular Tumoral , Conexina 26 , Conexina 43/genética , Femenino , Uniones Comunicantes/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática/patología , Proteína beta1 de Unión Comunicante
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