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PNAS 99 (4): 1842-1846

Copyright © 2002 by the National Academy of Sciences.


Ubiquitin-dependent mechanism regulates rapid turnover of AU-rich cytokine mRNAs

Gaurav Laroia*, Bedabrata Sarkar, and Robert J. Schneider{dagger}

Department of Microbiology, New York University School of Medicine, New York, NY 10016

Received for publication October 29, 2001.

Abstract: An AU rich element (ARE) in the 3' noncoding region promotes the rapid degradation of mammalian cytokine and proto-oncogene mRNAs, such as tumor necrosis factor-α, granulocyte–macrophage colony-stimulating factor (GM-CSF) and c-fos. Destabilization of ARE-mRNAs involves the association of ARE-binding proteins tristetraprolin or AUF1 and proteasome activity, of which the latter has not been characterized. Here, we show that the stability of a model short-lived mRNA containing the GM-CSF ARE was regulated by the level of ubiquitin-conjugating activity in the cell, which links ARE-mRNA decay to proteasome activity. Increased expression of a cytokine-inducible deubiquitinating protein (DUB) that impairs addition of ubiquitin to proteins fully blocked ARE-mRNA decay, whereas increased expression of a DUB that promotes ubiquitin addition to proteins strongly accelerated ARE-mRNA decay. ARE-mRNA turnover was found to be activated by the ubiquitin-addition reaction and blocked by the ubiquitin-removal reaction. Saturation of the ARE-mRNA decay machinery by high levels of ARE-mRNA, which is well established but not understood, was found to be relieved by increased expression of a DUB that promotes ubiquitin addition to proteins. Finally, inhibition of proteasome activity also blocked accelerated ARE-mRNA decay that is mediated by increased ubiquitin recycling. These results demonstrate that both ubiquitinating activity and proteasome activity are essential for rapid turnover of a model cytokine ARE-mRNA containing the GM-CSF ARE.

* Present address: McKinsey and Company, TAJ Palace Hotel, 2 Sardar Patel Marg, Diplomatic Enclave, New Delhi 110021, India.

{dagger} To whom reprint requests should be addressed at: Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, NY 10016. E-mail: schner01{at}

Edited by Anthony Cerami, The Kenneth S. Warren Institute, Kitchawan, NY, and approved December 17, 2001

This paper was submitted directly (Track II) to the PNAS office.

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