Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Sci. Signal., 27 October 2009
Vol. 2, Issue 94, p. ra69
[DOI: 10.1126/scisignal.2000442]

RESEARCH

Increased MKK4 Abundance with Replicative Senescence Is Linked to the Joint Reduction of Multiple MicroRNAs

Bernard S. Marasa1, Subramanya Srikantan1, Kiyoshi Masuda1, Kotb Abdelmohsen1, Yuki Kuwano1, Xiaoling Yang1, Jennifer L. Martindale1, Carrie W. Rinker-Schaeffer2, and Myriam Gorospe1*

1 Laboratory of Cellular and Molecular Biology, National Institute on Aging–Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
2 Department of Pathology, University of Chicago, Chicago, IL 60637, USA.

Abstract: MKK4 (mitogen-activated protein kinase kinase 4) is a pivotal upstream activator of c-Jun N-terminal kinase and p38. Here, we report that the abundance of MKK4 increases in senescent human diploid fibroblasts through enhanced translation. We identified four microRNAs (miR-15b, miR-24, miR-25, and miR-141) that target the MKK4 messenger RNA (mRNA); the abundance of these microRNAs decreased during replicative senescence. Individually modulating the amount of each microRNA did not modify MKK4 abundance, but their concomitant overexpression decreased and their joint reduction increased MKK4 abundance. Reporter analyses indicated that these microRNAs acted through the MKK4 5' and 3' untranslated regions. Elevated MKK4 abundance inhibited cell proliferation and increased the phosphorylation and activity of p38 and PRAK (p38-regulated/activated protein kinase). Thus, multiple microRNAs acting on a single target, the MKK4 mRNA, collectively influence MKK4 abundance during replicative senescence.

* To whom correspondence should be addressed. E-mail: myriam-gorospe{at}nih.gov

Citation: B. S. Marasa, S. Srikantan, K. Masuda, K. Abdelmohsen, Y. Kuwano, X. Yang, J. L. Martindale, C. W. Rinker-Schaeffer, M. Gorospe, Increased MKK4 Abundance with Replicative Senescence Is Linked to the Joint Reduction of Multiple MicroRNAs. Sci. Signal. 2, ra69 (2009).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Science Signaling Podcast: 27 October 2009.
M. Gorospe and A. M. VanHook (2009)
Science Signaling 2, pc19
   Abstract »    Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882