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LncRNA GUARDIN suppresses cellular senescence through a LRP130-PGC1?-FOXO4-p21-dependent signaling axis


ABSTRACT: The long non-coding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions towards senescence or apoptosis, but the underlying molecular signals are unknown. Here we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1?. GUARDIN acts as a scaffold to stabilize LRP130/PGC1? heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130 or PGC1? leads to increased expression of FOXO4 and upregulation of its target gene p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, an agent that suppresses cell senescence. FOS-Like Antigen 2 (FOSL2) acts as a transcriptional repressor of GUARDIN and lower FOSL2 levels in response to rapamycin correlate with increased levels of GUARDIN. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1?-FOXO4 signaling axis and moreover, GUARDIN contributes to the anti-senility activities of rapamycin.

SUBMITTER: Xuedan Sun 

PROVIDER: S-SCDT-EMBOR-2019-48796V1 | biostudies-other |

REPOSITORIES: biostudies-other

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