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Molecular and Cellular Biology, December 2006, p. 9196-9208, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00945-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel mRNA Targets for Tristetraprolin (TTP) Identified by Global Analysis of Stabilized Transcripts in TTP-Deficient Fibroblasts{triangledown} ,{dagger}

Wi S. Lai,1 Joel S. Parker,2 Sherry F. Grissom,3 Deborah J. Stumpo,1 and Perry J. Blackshear1,4,5*

Laboratory of Neurobiology,1 Microarray Group,3 Office of Clinical Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709,4 Constella Group, Durham, North Carolina 27709,2 Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 277105

Received 29 May 2006/ Returned for modification 8 July 2006/ Accepted 22 September 2006

Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice and cells derived from them showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and destruction. Known physiological target mRNAs for TTP include tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and interleukin-2ß. Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment. Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained two or more conserved TTP binding sites; nine of these appeared to be stabilized on Northern blots. The most dramatically affected transcript encoded the protein Ier3, recently implicated in the physiological control of blood pressure. The Ier3 transcript contained several conserved TTP binding sites that could bind TTP directly and conferred TTP sensitivity to the mRNA in cell transfection studies. These studies have identified several new, physiologically relevant TTP target transcripts in fibroblasts; these target mRNAs encode proteins from a variety of functional classes.

* Corresponding author. Mailing address: A2-05 NIEHS, 111 Alexander Dr., Research Triangle Park, NC 27709. Phone: (919) 541-4899. Fax: (919) 541-4571. E-mail: Black009{at}niehs.nih.gov.

{triangledown} Published ahead of print on 9 October 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2006, p. 9196-9208, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.00945-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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