KRAS and NRAS Translation Is Increased upon MEK Inhibitors-Induced Processing Bodies Dissolution

Autor: Brest, Olivia Vidal-Cruchez, Victoria J. Nicolini, Tifenn Rete, Karine Jacquet, Roger Rezzonico, Caroline Lacoux, Marie-Angela Domdom, Barnabé Roméo, Jérémie Roux, Arnaud Hubstenberger, Bernard Mari, Baharia Mograbi, Paul Hofman, Patrick
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Cancers; Volume 15; Issue 12; Pages: 3078
ISSN: 2072-6694
DOI: 10.3390/cancers15123078
Popis: Overactivation of the mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies directly targeting this pathway lead to cancer drug resistance. Resistance has been linked to compensatory RAS overexpression, but the mechanisms underlying this response remain unclear. Here, we find that MEK inhibitors (MEKi) are associated with an increased translation of the KRAS and NRAS oncogenes through a mechanism involving dissolution of processing body (P-body) biocondensates. This effect is seen across different cell types and is extremely dynamic since removal of MEKi and ERK reactivation result in reappearance of P-bodies and reduced RAS-dependent signaling. Moreover, we find that P-body scaffold protein levels negatively impact RAS expression. Overall, we describe a new feedback loop mechanism involving biocondensates such as P-bodies in the translational regulation of RAS proteins and MAPK signaling.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje