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Papers In Press, published online ahead of print March 8, 2002
J. Biol. Chem, 10.1074/jbc.M110465200
Submitted on October 31, 2001
Revised on January 30, 2002
Accepted on March 7, 2002

Cytoplasmic localization of Tristetraprolin involves 14-3-3-dependent and –independent mechanisms

Barbra A. Johnson, Justine R. Stehn, Michael B. Yaffe, and T. Keith Blackwell

Harvard Medical School, Center for Blood Research, Boston, MA 02115

Corresponding Author: blackwell{at}cbr.med.harvard.edu

The immediate early gene tristetraprolin (TTP) is induced transiently in many cell types by numerous extracellular stimuli. TTP encodes a zinc finger protein that can bind and destabilize mRNAs that encode tumor necrosis factor-alpha (TNFalpha) and other cytokines. We hypothesize that TTP also has a broader role in growth-factor responsive pathways. In support of this model, we have previously determined that TTP induces apoptosis through the mitochondrial pathway, analogously to certain oncogenes and other immediate-early genes, and that TTP sensitizes cells to the pro-apoptotic signals of TNFalpha. In this study, we show that TTP and the related proteins TIS11b and TIS11d bind specifically to 14-3-3 proteins, and that individual 14-3-3 isoforms preferentially bind to different phosphorylated TTP species. 14-3-3 binding does not appear to inhibit or promote induction of apoptosis by TTP, but is one of multiple mechanisms that localize TTP to the cytoplasm. Our results provide the first example of 14-3-3 interacting functionally with an RNA binding protein, and binding in vivo to a Type II 14-3-3 binding site. They also suggest that 14-3-3 binding is part of a complex network of stimuli and interactions that regulate TTP function.


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