RT Journal Article
T1 The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies.
A1 Aguilar Garrido, Pedro
A1 Velasco Estévez, María
A1 Navarro Aguadero, Miguel Ángel
A1 Otero Sobrino, Álvaro
A1 Ibáñez Navarro, Marta
A1 Marugal, Miguel Ángel
A1 Hernández Sánchez, María
A1 Malaney, Prerna
A1 Rodriguez, Ashley
A1 Benitez, Oscar
A1 Zhang, Xiaroui
A1 Aitken, Marisa Jl
A1 Ortiz Ruiz, Alejandra
A1 Megías, Diego
A1 Pérez, Manuel
A1 Mata, Gadea
A1 Gomez, Jesús
A1 Lafarga, Miguel
A1 Domínguez, Orlando
A1 Graña-Castro, Osvaldo
A1 Caleiras, Eduardo
A1 Ximénez-Embun, Pilar
A1 Isasa, Marta
A1 Andrés Gamazo, Paloma Jimena de
A1 Rodríguez Perales, Sandra
A1 Torres Ruiz, Raúl
A1 Revilla, Enrique
A1 García Martín, Rosa María
A1 Azorín, Daniel
A1 Zubicaray, Josune
A1 Sevilla, Julián
A1 Sirozh, Oleksandra
A1 Lafarga, Vanesa
A1 Martínez López, Joaquín
A1 Post, Sean M
A1 Gallardo, Miguel
AB The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation as the HNRNPK overexpression caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell cycle arrest, senescence, and bone marrow failure phenotype, similar to what is observed in patients with ribosomopathies. Together, our findings identify HNRNPK as a master regulator of ribosome biogenesis and nucleolar homeostasis through p53, providing what we believe to be a new perspective on the orchestration of nucleolar integrity, ribosome function and cellular senescence.
PB American Society for Clinical Investigation
SN 0021-9738
YR 2025
FD 2025-05-08
LK https://hdl.handle.net/20.500.14352/122603
UL https://hdl.handle.net/20.500.14352/122603
LA eng
NO Aguilar-Garrido, P., Velasco-Estévez, M., Navarro-Aguadero, M. Á., Otero-Sobrino, Á., Ibáñez-Navarro, M., Marugal, M. Á., Hernández-Sánchez, M., Malaney, P., Rodriguez, A., Benitez, O., Zhang, X., Aitken, M. J., Ortiz-Ruiz, A., Megías, D., Pérez, M., Mata, G., Gomez, J., Lafarga, M., Domínguez, O., Graña-Castro, O., … Gallardo, M. (2025). The tumor suppressor HNRNPK induces p53-dependent nucleolar stress to drive ribosomopathies. The Journal of clinical investigation, 135(12), e183697. https://doi.org/10.1172/JCI183697
NO Author contributions: MG conceived and planned the study with input from SMP, PM, XZ, MJLA, and JML. PAG, MVE, MANA, AOS, AOR, and MAM designed and performed the culture, cellular, and molecular biology experiments as well as in vivo experiments. MIN designed and performed FCM experiments. MHS and RTR designed and performed the CRISPR-modified cellular models. AR, OB, and SMP performed Northern blotting. PAG, with help from DM, MP, GM, JG, OS, and VL, designed and performed the confocal microscopy experiments. ML designed and performed electron microscopy experiments. OD and OGC designed and performed the RNA-Seq experiments. EC and PJDA designed and performed the IHC mice experiments. JZ, JS, DA, RMGM, and ER obtained patient samples and clinical information and performed the IHC experiments. PXE and MI designed and performed TMTpro experiments. SRP and RTR designed and performed karyotyping experiments. MG wrote the manuscript with the contributions from MVE and PAG. MG supervised the study. All authors approved the final manuscript.
NO Instituto de Salud Carlos III
NO Unión Europea
NO Fundación CRIS contra el Cáncer
NO Asociación Española contra el Cáncer (AECC)
DS Docta Complutense
RD 20 jul 2025