RESEARCH PAPER


NF90 coordinately represses the senescence-associated secretory phenotype

Kumiko Tominaga-Yamanaka1, Kotb Abdelmohsen1, Jennifer L. Martindale1, Xiaoling Yang1, Dennis D. Taub2, and Myriam Gorospe1
1 Laboratory of Genetics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
2 Laboratory of Molecular Biology and Immunology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
Key words:
RNA-binding protein, ribonucleoprotein complex, mRNA translation, mRNA stability, post-transcriptional gene regulation, senescence
Abbreviations:
CR, coding region; pdl, population doubling; RBP, NF90, nuclear factor 90; RNA-binding protein; RNP, ribonucleoprotein; UTR, untranslated region
Received:
10/20/12; Accepted: 10/30/12; Published: 10/31/12
Correspondence:

Abstract

A hallmark trait of cellular senescence is the acquisition of a senescence-associated secretory phenotype (SASP). SASP factors include cytokines and their receptors (IL-6, IL-8, osteoprotegerin, GM-CSF), chemokines and their ligands (MCP-1, HCC4), and oncogenes (Gro1 and Gro2), many of them encoded by mRNAs whose stability and translation are tightly regulated. Using two models of human fibroblast senescence (WI-38 and IDH4 cells), we report the identification of RNA-binding protein NF90 as a post-transcriptional repressor of several SASP factors. In ‘young', proliferating fibroblasts, NF90 was highly abundant, associated with numerous SASP mRNAs, and inhibited their expression. By contrast, senescent cells expressed low levels of NF90, thus allowing SASP factor expression to increase. NF90 elicited these effects mainly by repressing the translation of target SASP mRNAs, since silencing NF90 did not increase the steady-state levels of SASP mRNAs but elevated key SASP factors including MCP-1, GROa, IL-6, and IL-8. Our findings indicate that NF90 contributes to maintaining low levels of SASP factors in non-senescent cells, while NF90 reduction in senescent cells allows SASP factor expression to rise.