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Molecular and Cellular Biology, September 2001, p. 5778-5789, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5778-5789.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Parallel and Independent Regulation of Interleukin-3 mRNA Turnover by Phosphatidylinositol 3-Kinase and p38 Mitogen-Activated Protein Kinase

Xiu-Fen Ming, Georg Stoecklin, Min Lu, Renate Looser, and Christoph Moroni*

Institute for Medical Microbiology, University of Basel, Basel, Switzerland

Received 13 December 2000/Returned for modification 8 March 2001/Accepted 30 May 2001

AU-rich elements (ARE) present in the 3' untranslated regions of many cytokines and immediate-early genes are responsible for targeting the transcripts for rapid decay. We present evidence from cotransfection experiments in NIH 3T3 cells that two signaling pathways, one involving phosphatidylinositol 3-kinase (PI3-K), and one involving the p38 mitogen-activated protein kinase (MAPK), lead to stabilization of interleukin-3 mRNA in parallel. Stabilization mediated by either of the two pathways was antagonized by tristetraprolin (TTP), an AU-binding protein known to promote constitutive decay of ARE-containing transcripts. Remarkably, the stabilizing AU-binding protein HuR, in collaboration with p38 MAPK but not with PI3-K, could overcome the destabilizing effect of TTP. These data argue that the stabilizing kinases PI3-K and p38 MAPK do not act through direct inactivation of TTP but via activating pathway-specific stabilizing AU-binding proteins. Our data suggest an integrated model of mRNA turnover control, where stabilizing (HuR) and destabilizing (TTP) AU-binding proteins compete and where the former are under the positive control of independent phosphokinase signaling pathways.

* Corresponding author. Mailing address: Institute for Medical Microbiology, University of Basel, Basel, Switzerland. Phone: 41-61-267 32 64. Fax: 41-61-267 32 98. E-mail: christoph.moroni{at}unibas.ch.

Molecular and Cellular Biology, September 2001, p. 5778-5789, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.5778-5789.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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